O-6-benzylguanine: A clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directrd DNA repair

Citation
Tp. Spiro et al., O-6-benzylguanine: A clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directrd DNA repair, CANCER RES, 59(10), 1999, pp. 2402-2410
Citations number
48
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
59
Issue
10
Year of publication
1999
Pages
2402 - 2410
Database
ISI
SICI code
0008-5472(19990515)59:10<2402:OACTET>2.0.ZU;2-I
Abstract
Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish approp riate dosing schedules, To establish a biochemical efficacy end point for o vercoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resis tance to 1,3-bis(2-chloroethyl)-1-nitrosourea. we performed a novel dose es calation clinical trial for the AGT-depleting agent O-6-benzylguanine (BG). The dose of BG required to deplete AGT to undetectable levels (BMDT) in se quential computed tomography-guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty patients received doses of BG ranging fro m 10 to 120 mg/m(2). In tumor tissue, AGT depletion >86% of baseline was de monstrated at all doses tested. Residual tumor AGT activity, present 18 h a fter BC doses of 10-80 mg/m(2), was eliminated at the 120 mg/m(2) dose and is thus the BMDT of BG, BG pharmacokinetics are characterized by the rapid, dose-independent clearance of BG from plasma, Metabolism of BG to its biol ogically active metabolite, 8-oxo-benzylguanine (8-oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG, Plasma concentrations of 8-oxo-BG wel l above 200 ng/ml 18 h after the end of the BG infusion a ere observed at t he highest dose levels tested and appeared to correlate with depiction of A GT activity to undetectable levels in tumor tissue. AGT activity in periphe ral blood mononuclear cells at baseline did not correlate with tumor tissue AGT activity, Depletion of AGT activity to undetectable levels in peripher al blood mononuclear cells occurred at lower doses and was not a reliable p redictor for tumor tissue depletion. No serious side effects were observed with administration of BG alone or in combination with 13 mg/m(2) 1,3-bis(2 -chloroethyl)-1-nitrosourea. This is the first clinical study in which bioc hemical analyses from pre- and posttreatment tumor biopsies have been used as an efficacy end point for the clinical development of an anticancer agen t. From our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m(2) infused over 1 h should be used in Phase II clinical trials.