Biologic Activity of a Nucleotide Conjugate Between Mitomycin C and Cytarabine Monophosphate |
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| Authors: | Robert T Dorr Ph D h James D Liddil M S Bhashyam S lyengar Ph D h Alan F List M D William A Remers PhD h |
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| Institution: | 1. the College of Medicine, Department of Pharmacology, University of Arizona , Tucson, AZ, U.S.A.;2. Arizona Cancer Center, 1515 N. Campbell Avenue , Tucson, AZ, 85724;3. the College of Medicine, Department of Pharmacology, University of Arizona , Tucson, AZ, U.S.A.;4. the College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ, U.S.A.;5. the College of Medicine, Department of Internal Medicine, University of Arizona , Tucson, AZ, U.S.A. |
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| Abstract: | Abstract A dual prodrug conjugate between the antimetabolite cytarabine monophosphate and the alkylating agent 2,7-diaminomitosene (derived from mitomycin C), cytaramycin, was synthesized and tested for antileukemic activity in sensitive and resistant tumors. The compound was active against parental L-1210, CCRF-CEM, HL-60 and K-562 leukemia cells but did not overcome resistance in sublines developed for (1) multidrug resistance (L-1210/MDR and K-562-R) or (2) for cytarabine resistance (CCRF-CEM/ARA-C and HL-60/ARA-C). Alkaline DNA elution tests demonstrate a predominance of strand breaking activity due to the cytarabine moiety, and a lesser degree of DNA crosslinking, due to the mitosene moiety. The conjugate was active in mice bearing P-388 leukemia (80% increased lifespan), but was not more effective than mitomycin C alone in mice bearing a cytarabine-resistant L-1210 cell line (38% to 31% increased lifespan). These findings suggest that mitomycin nucleotide conjugates do not overcome resistance to the parent antimetabolites. |
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