Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model.
The purpose of the present study was to examine the effect of O6-benzylguanine (O6-BG) on the antitumour activity and toxicity of 8-carbamoyl-3-methylimidazo [5, 1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) in a human malignant melanoma xenograft model following single and multiple administration of the combination. O6-BG irreversibly inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which confers resistance to temozolomide. Preadministration of O6-BG (35 mg/kg, i.p.) 1 h prior to temozolomide (i.p.) was examined using single and daily x5 dosing regimens in athymic mice bearing subcutaneous A375P xenografts. The AGT activity of A375P tumors was 95 +/- 8 fmol/mg protein (mean +/- SE, n = 4). O6-BG alone completely suppressed xenograft AGT activity within 1 h of administration but had no effect upon tumor growth. O6-BG did not significantly increase the tumor growth delay induced by a single 200-mg/ kg dose of temozolomide (P > 0.05, two-tailed Mann-Whitney test) but did increase the associated mean body weight loss (P < 0.025). In contrast, when the same dose of temozolomide was divided into five equal fractions (40 mg/kg) and given with O6-BG on 5 consecutive days, a comparable increase in toxicity was accompanied by a very significant increase in tumor growth delay (P < 0.0025), equivalent to that produced by a 3-fold greater dose of temozolomide alone. O6-BG with temozolomide also produced a greater antitumour effect than an equitoxic dose of temozolomide alone on this schedule (P < 0.005). These data indicate that the enhancement of temozolomide antitumour activity by O6-BG preadministration is dependent upon the schedule of drug administration, with multiple dosing of O6-BG + temozolomide producing the greatest effect. The results also suggest that prolonged administration of the combination can lead to an increase in the therapeutic index of temozolomide.
Wedge
S R
SR
Department of Medical Oncology, Charing Cross Hospital, London, UK.
Porteous
J K
JK
Newlands
E S
ES
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D004334:Drug Administration Schedule; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008780:Methyltransferases / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide