char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = -;code = 45
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = l;code = 108
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = x;code = 120
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = ;code = 32
char = I;code = 73
char = .;code = 46
char = ;code = 32
char = R;code = 82
char = e;code = 101
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = .;code = 46
result sql = The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine.
The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine.
char = R;code = 82
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = c;code = 99
char = u;code = 117
char = m;code = 109
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = u;code = 117
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = x;code = 120
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = l;code = 108
char = y;code = 121
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = b;code = 98
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = c;code = 99
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = k;code = 107
char = n;code = 110
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = m;code = 109
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = H;code = 72
char = o;code = 111
char = w;code = 119
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = m;code = 109
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = r;code = 114
char = u;code = 117
char = g;code = 103
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = ;code = 32
char = (;code = 40
char = e;code = 101
char = .;code = 46
char = g;code = 103
char = .;code = 46
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = T;code = 84
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = I;code = 73
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = e;code = 101
char = .;code = 46
char = g;code = 103
char = .;code = 46
char = ;code = 32
char = D;code = 68
char = o;code = 111
char = x;code = 120
char = o;code = 111
char = r;code = 114
char = u;code = 117
char = b;code = 98
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = M;code = 77
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = A;code = 65
char = M;code = 77
char = S;code = 83
char = A;code = 65
char = );code = 41
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = o;code = 111
char = r;code = 114
char = k;code = 107
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = y;code = 121
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = (;code = 40
char = p;code = 112
char = i;code = 105
char = -;code = 45
char = p;code = 112
char = i;code = 105
char = );code = 41
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = w;code = 119
char = o;code = 111
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = -;code = 45
char = k;code = 107
char = n;code = 110
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = :;code = 58
char = ;code = 32
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = d;code = 100
char = (;code = 40
char = Q;code = 81
char = M;code = 77
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ,;code = 44
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = d;code = 100
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = c;code = 99
char = h;code = 104
char = l;code = 108
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = N;code = 78
char = M;code = 77
char = 2;code = 50
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = d;code = 100
char = );code = 41
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ';code = 39
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = H;code = 72
char = L;code = 76
char = -;code = 45
char = 6;code = 54
char = 0;code = 48
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = N;code = 78
char = M;code = 77
char = 2;code = 50
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = b;code = 98
char = s;code = 115
char = o;code = 111
char = r;code = 114
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = o;code = 111
char = r;code = 114
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = U;code = 85
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = y;code = 121
char = n;code = 110
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = ";code = 34
char = n;code = 110
char = e;code = 101
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = b;code = 98
char = o;code = 111
char = r;code = 114
char = h;code = 104
char = o;code = 111
char = o;code = 111
char = d;code = 100
char = ";code = 34
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = o;code = 111
char = c;code = 99
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = (;code = 40
char = A;code = 65
char = C;code = 67
char = );code = 41
char = =;code = 61
char = 5;code = 53
char = 9;code = 57
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 2;code = 50
char = M;code = 77
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = D;code = 68
char = e;code = 101
char = l;code = 108
char = t;code = 116
char = a;code = 97
char = H;code = 72
char = (;code = 40
char = 0;code = 48
char = ';code = 39
char = );code = 41
char = =;code = 61
char = -;code = 45
char = 1;code = 49
char = 1;code = 49
char = 6;code = 54
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = );code = 41
char = ;;code = 59
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = v;code = 118
char = o;code = 111
char = r;code = 114
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = D;code = 68
char = e;code = 101
char = l;code = 108
char = t;code = 116
char = a;code = 97
char = S;code = 83
char = (;code = 40
char = 0;code = 48
char = ';code = 39
char = );code = 41
char = =;code = 61
char = 7;code = 55
char = .;code = 46
char = 7;code = 55
char = 2;code = 50
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = K;code = 75
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = o;code = 111
char = c;code = 99
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = );code = 41
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = G;code = 71
char = i;code = 105
char = b;code = 98
char = b;code = 98
char = s;code = 115
char = ';code = 39
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = g;code = 103
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = -;code = 45
char = C;code = 67
char = A;code = 65
char = F;code = 70
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = D;code = 68
char = e;code = 101
char = l;code = 108
char = t;code = 116
char = a;code = 97
char = G;code = 71
char = (;code = 40
char = 0;code = 48
char = ';code = 39
char = );code = 41
char = =;code = 61
char = -;code = 45
char = 2;code = 50
char = .;code = 46
char = 4;code = 52
char = 1;code = 49
char = k;code = 107
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = .;code = 46
char = ;code = 32
char = W;code = 87
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = n;code = 110
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = N;code = 78
char = M;code = 77
char = 2;code = 50
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = s;code = 115
char = c;code = 99
char = o;code = 111
char = p;code = 112
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = o;code = 111
char = r;code = 114
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ;code = 32
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = y;code = 121
char = ;code = 32
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = n;code = 110
char = -;code = 45
char = a;code = 97
char = l;code = 108
char = k;code = 107
char = y;code = 121
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = -;code = 45
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = Q;code = 81
char = );code = 41
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = d;code = 100
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = H;code = 72
char = L;code = 76
char = -;code = 45
char = 6;code = 54
char = 0;code = 48
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = N;code = 78
char = M;code = 77
char = 2;code = 50
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = Q;code = 81
char = M;code = 77
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = );code = 41
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = (;code = 40
char = A;code = 65
char = C;code = 67
char = );code = 41
char = =;code = 61
char = 7;code = 55
char = 5;code = 53
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 3;code = 51
char = M;code = 77
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = );code = 41
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = u;code = 117
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = c;code = 99
char = o;code = 111
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = );code = 41
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = ";code = 34
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ";code = 34
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = k;code = 107
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = M;code = 77
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = );code = 41
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = w;code = 119
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = u;code = 117
char = r;code = 114
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = x;code = 120
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = i;code = 105
char = d;code = 100
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = d;code = 100
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = c;code = 99
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
result sql = Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.

Publication: Biochem. Pharmacol. 2002 Feb 15 ;63(4)::625-34.
Publication Date: 2002 Feb 15
Study Author(s): Kapuscinski, Jan;Ardelt, Barbara;Piosik, Jacek;Zdunek, Malgorzata;Darzynkiewicz, Zbigniew;
Institution: Laboratory of Biophysical Chemistry, Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822, Gdansk, Poland. [email protected]
Shortcut link to this study:
Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.
PMID: 11992630

Have comments? Post them here:

comments powered by Disqus

Get breaking news about nutritional cures, dangerous chemicals, superfoods . and more.

Subscribe to the FREE Natural News email newsletter. Your privacy is protected.