title: Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro.
abstract: Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.
authors.affiliation: Division of Biology, Kansas State University, Manhattan.
authors.forename: K
authors.initials: K
authors.lastname: Satyamoorthy
authors.forename: S S
authors.initials: SS
authors.lastname: Deshpande
authors.forename: M P
authors.initials: MP
authors.lastname: Chitnis
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D016590:Aphidicolin; D003561:Cytarabine / Q000494:pharmacology; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004224:Diterpenes; D012334:RNA, Neoplasm; D003561:Cytarabine; D016590:Aphidicolin; C007390:inosine dialdehyde; D007288:Inosine; D004317:Doxorubicin; D012264:Ribonucleotide Reductases; D004257:DNA Polymerase II; C044466:caracemide; D006918:Hydroxyurea