High levels of O-6-alkylguanine-DNA-alkyltransferase (OGAT) can, at le
ast in part, account for tumor cell resistance to O-6-alkylguanine alk
ylating agents, including triazene compounds. A pilot clinical study i
ndicates that dacarbazine can induce a marked decrease of leukemic bla
sts in patients affected by acute myelogenous leukemia (AML) with low
pretreatment levels of OGAT activity. In this study we show a synergis
tic antitumor effect between cisplatin (CDDP) and temozolomide (an in
vitro active analog of dacarbazine), following combined in vitro treat
ment of leukemic blasts. Synergistic effect appears to be CDDP-dose de
pendent. In vivo treatment of leukemic patients with CDDP was followed
by a reduction of OGAT activity in 2 out 3 cases. These data point ou
t that CDDP could be a good candidate for depleting OGAT protein of le
ukemic cells, thus reversing tumor cell resistance to dacarbazine.