Abstract
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.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Blast Crisis / drug therapy
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Blast Crisis / enzymology
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Cisplatin / administration & dosage
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Cisplatin / therapeutic use*
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Dacarbazine / administration & dosage
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Dacarbazine / analogs & derivatives
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Dacarbazine / therapeutic use
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Dose-Response Relationship, Drug
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Drug Synergism
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Female
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Humans
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In Vitro Techniques
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Leukemia / drug therapy*
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Leukemia / enzymology
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Leukemia, Megakaryoblastic, Acute / drug therapy
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Leukemia, Megakaryoblastic, Acute / enzymology
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myelomonocytic, Acute / drug therapy
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Leukemia, Myelomonocytic, Acute / enzymology
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Male
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Methyltransferases / metabolism
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Middle Aged
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O(6)-Methylguanine-DNA Methyltransferase
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Pilot Projects
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Remission Induction
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Temozolomide
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Treatment Outcome
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Triazenes / administration & dosage
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Triazenes / pharmacology
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Triazenes / therapeutic use*
Substances
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Triazenes
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Dacarbazine
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Methyltransferases
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O(6)-Methylguanine-DNA Methyltransferase
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Cisplatin
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Temozolomide