Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
DRUG SYNERGISM, ANTAGONISM, AND COLLATERAL SENSITIVITY INVOLVING GENETIC CHANGES
Synergism and Antagonism in Chemotherapy. Chou TC and Rideout DC, eds. New York, Academic, p. 585-619, 1991.. Unique Identifier : AIDSLINE ICDB/92678590 Avramis VI; Huang SH; Holcenberg JS; Div. of Hematology-Oncology, Children's Hosp. of Los Angeles,; Univ. of Southern California, P.O. Box 54700, Los Angeles, CA; 90054-0070
Abstract:
Drug synergism is defined as a significant improvement in pharmacologic action when two or more drugs are used in combination. Drug antagonism is defined as a reduced pharmacologic effect when two or more drugs are administered in combination. The actions of drugs will be altered when specific gene products that control their transport, activation, degradation, and binding to targets are expressed in abnormal quantities. Genetic alterations often lead to drug resistance and failure of cancer chemotherapy. Major genetic changes that affect the action of anticancer drugs are reviewed, with emphasis on studies conducted by the authors on the effects of cytosine arabinoside (araC) and 5-azacytidine (5-azaC) on methylation of DNA and activity of nucleoside analogs. Topics include over-expression of genes; under-expression of genes (altered DNA methylation patterns, deoxycytidine 'silencing' conferring drug resistance to araC in leukemic cells, activation of 5-azaC and congeners to induce DNA hypomethylation and deoxycytidine kinase [dCK] reexpression in human leukemic cell lines, accumulation and kinetics of araC in plasma and araCTP in leukemic cells, dCK and cytidine deaminase activities in leukemic cells of pediatric patients [pts], pharmacodynamic modeling of araC administration, determination of in vivo DNA methylation levels in pts' leukemic cells, partial reversal of tumor drug resistance to high-dose araC, effect of 5-azaC treatment on the expression of oncogenes, in vivo development of tumor resistance to araC and correlation of DNA methylation patterns in a pediatric pt with acute lymphoblastic leukemia, and cloning of human dCK); and collateral sensitivity (drug synergism studies between fludarabine phosphate [F-araA(MP)] and araC, in vivo treatment with F-araA(MP), and drug synergism studies between anti-HIV drugs [zidovudine and dideoxyinosine]). (52 Refs)
Keywords: Animal Antineoplastic Agents, Combined/*PHARMACOLOGY Cell Line Cell Survival/*DRUG EFFECTS Cell Transformation, Neoplastic/DRUG EFFECTS/*GENETICS Child Drug Interactions DNA Damage/*DRUG EFFECTS/GENETICS DNA Repair/*DRUG EFFECTS/GENETICS Gene Expression Regulation, Neoplastic/*DRUG EFFECTS Human Leukemia Tumor Cells, Cultured/*DRUG EFFECTS MONOGRAPH REVIEW
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
