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Effect of single and multiple administration of an O 6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model

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The purpose of the present study was to examine the effect of O 6-benzylguanine (O 6-BG) on the antitumour activity and toxicity of 8-carbamoyl-3-methylimidazo [5, 1-d ] -1,2,3,5-tetrazine-4(3H)-one (temo-zolomide) in a human malignant melanoma xenograft model following single and multiple administration of the combination. O 6-BG irreversibly inactivates the DNA-repair protein O 6-alkylguanine-DNA alkyltransferase (AGT), which confers resistance to temozolomide. Preadministration of O 6-BG (35 mg/kg, i.p.) 1 h prior to temozolomide (i.p.) was examined using single and daily × 5 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). O 6-BG alone completely suppressed xenograft AGT activity within 1 h of administration but had no effect upon tumor growth. O 6-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 O 6-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. O 6-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 O 6-BG preadministration is dependent upon the schedule of drug administration, with multiple dosing of O 6-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.

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Received: 8 September 1996 / Accepted: 8 February 1997

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Wedge, S., Porteous, J. & Newlands, E. Effect of single and multiple administration of an O 6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model. Cancer Chemother Pharmacol 40, 266–272 (1997). https://doi.org/10.1007/s002800050657

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  • DOI: https://doi.org/10.1007/s002800050657

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