This study investigated whether the therapeutic index of regional
melanoma therapy using parenteral
temozolomide could be improved by chemomodulation with
O6-benzylguanine (O6BG), an inhibitor of the
DNA repair enzyme O6-alkylguanine-DNA
alkyltransferase (AGT). Using a nude rat s.c. human
melanoma xenograft model of the extremity,
tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10%
DMSO in PBS (control),
temozolomide alone, or
temozolomide in conjunction with single or multiple doses of i.p. O6BG.
Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted
tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional
temozolomide alone (350 mg/kg), systemic
temozolomide with O6BG, or vehicle combined with O6BG showed no significant
tumor responses compared with controls. Whereas use of regional
temozolomide alone at a higher dose (750 mg/kg) showed some degree of
tumor response, regional
temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in
tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with
temozolomide regional
chemotherapy leads to a significant improvement in
melanoma antitumor responses. Clinical trials using
chemotherapy modulation may improve response rates in future regional infusion and perfusion
drug trials.