Cisplatin increases sensitivity of human leukemic blasts to triazene compounds.
High levels of O6-alkylguanine-DNA-alkyltransferase (OGAT) can, at least in part, account for tumor cell resistance to O6-alkylguanine alkylating agents, including triazene compounds. A pilot clinical study indicates that dacarbazine can induce a marked decrease of leukemic blasts in patients affected by acute myelogenous leukemia (AML) with low pretreatment levels of OGAT activity. In this study we show a synergistic antitumor effect between cisplatin (CDDP) and temozolomide (an in vitro active analog of dacarbazine), following combined in vitro treatment of leukemic blasts. Synergistic effect appears to be CDDP-dose dependent. In vivo treatment of leukemic patients with CDDP was followed by a reduction of OGAT activity in 2 out 3 cases. These data point out that CDDP could be a good candidate for depleting OGAT protein of leukemic cells, thus reversing tumor cell resistance to dacarbazine.
Piccioni
D
D
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
D'Atri
S
S
Papa
G
G
Caravita
T
T
Franchi
A
A
Bonmassar
E
E
Graziani
G
G
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy / Q000201:enzymology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010865:Pilot Projects; D012074:Remission Induction; D000077204:Temozolomide; D016896:Treatment Outcome; D014226:Triazenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D014226:Triazenes; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D000077204:Temozolomide