Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model.

Abstract

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.

• Authors: S R Wedge, J K Porteous, E S Newlands
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 40 Issue 3 Pg. 266-72 ( 1997) ISSN: 0344-5704 [Print] Germany
• PMID: 9219512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Alkylating
• O(6)-benzylguanine
• Guanine
• Dacarbazine
• Methyltransferases
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (administration & dosage, toxicity)
• Antineoplastic Agents, Alkylating (administration & dosage, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Dacarbazine (administration & dosage, analogs & derivatives, toxicity)
• Drug Administration Schedule
• Guanine (administration & dosage, analogs & derivatives, toxicity)
• Humans
• Melanoma, Experimental (drug therapy, metabolism)
• Methyltransferases (drug effects, metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide
• Tumor Cells, Cultured