Jkv. Willson et al., MODULATION OF O-6-ALKYLGUANINE ALKYLTRANSFERASE DIRECTED DNA-REPAIR IN METASTATIC COLON CANCERS, Journal of clinical oncology, 13(9), 1995, pp. 2301-2308
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.