MODULATION OF O-6-ALKYLGUANINE ALKYLTRANSFERASE DIRECTED DNA-REPAIR IN METASTATIC COLON CANCERS

Purpose: Carmustine(BCNU) resistance has been correlated tumor express ion of the DNA repair enzyme O-6-alkylguanine-DNA alkyltransferase (AT ). It has been shown that streptozotocin will deplete AT activity of h uman colon cancer cells in vitro and potentiate BCNU cytotoxicity. Thi s clinical trial was conducted to determine whether streptozotocin can be used as a modulator of At in metastatic colorectal cancers and the reby overcome clinical resistance to BCNU. Patients and Methods: Fifte en patients with fluorouracil-resistant metastatic colon or rectal can cers were treated sequentially with 2 g/m(2) of streptozotocin followe d 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozo tocin depletes tumor AT. peripheral-blood mononuclear cells (PBMCs) we re evaluated as a surrogate tissue for prediction of baseline AT level s and streptozotocin posttreatment modulation of the AT in metastases. Results: Streptozotocin treatment led to a 78% (range, 69% to 89%) de crease in the AT levels in colon cancer metastases; however, myelosupp ression and hepatic toxicity limited the BCNU dose to 130 mg/m(2). A s imilar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were n ot predictive of the levels expressed in metastases from the same pati ent. Despite the decrease in tumor levels of AT, no clinical responses were observed. Conclusion: Streptozotocin decreases but does not full y deplete AT activity in metastatic colorectal cancers and the residua l AT level in metastases is sufficient to maintain clinical resistance to BCNU, We have also demonstrated that sequential computed tomograph y (CT)-directed biopsies of colorectal cancer metastases can be used t o evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modul ation achieved in the metastatic tumor. (C) 1995 by American Society o f Clinical Oncology.