Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
SELECTIVE SYNERGISM AGAINST THE TARGET VERSUS HOST BONE MARROW PROGENITOR CELLS
Synergism and Antagonism in Chemotherapy. Chou TC and Rideout DC, eds. New York, Academic, p. 715-37, 1991.. Unique Identifier : AIDSLINE ICDB/92678594 Berman E; Chang TT; Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, New; York, NY 10021
Abstract:
Clinical drug trials designed to assess synergy in vivo are difficult to interpret given such variables as drug absorption, protein binding, and metabolic degradation pathways. A quantitative approach to data interpretation in both infectious disease studies and oncology may prove useful to the clinician designing combination drug trials. Two major types of study are reviewed and discussed: synergistic effects of azidothymidine (AZT) and recombinant interferon-alpha (rIFN-alpha) against HIV vs normal human bone marrow progenitor cells and comparative cytotoxicity of different drug combinations against human leukemia cells vs normal hematopoietic precursors. Topics include data analysis using the multiple-drug-effect equation and median-effect equation; effect of AZT and rIFN-alpha2a as single agents; comparison of plasma drug levels, marrow inhibition, and inhibition of HIV-1 replication; and recommendations for clinical testing of AZT and rIFN-alpha2a. High doses of AZT and rIFN-alpha2a when given together far exceed what is necessary to inhibit HIV-1 replication and such doses are extremely toxic to the bone marrow. Based on these data, it can be suggested that a dose reduction of each drug would not compromise antiviral activity but would substantially reduce dose-limiting hematologic toxicity. In studies with Adriamycin and 4-hydroperoxycyclophosphamide (4-HC), it was determined that differences in the ratio of the combination affected both antitumor effect (HL-60 cells) and bone marrow toxicity. The combination of 4-HC with etoposide was synergistic in killing HL-60 cells, but relatively marrow sparing. The median-effect equation and combination index have been used in various in vitro model systems with potential clinical applications. This method of analysis is particularly relevant in oncology. This approach should be incorporated into the clinician's methodology for planning clinical trials. (43 Refs)
Keywords: Animal Antineoplastic Agents, Combined/*THERAPEUTIC USE Bone Marrow/*DRUG EFFECTS Bone Marrow Transplantation Cell Line Combined Modality Therapy Cytokines/PHARMACOLOGY Drug Synergism Hematopoietic Stem Cells/*DRUG EFFECTS Human HIV-1/DRUG EFFECTS Interferon Alfa-2a/PHARMACOLOGY Neoplasms/*DRUG THERAPY Tumor Cells, Cultured/*DRUG EFFECTS Virus Replication/DRUG EFFECTS Zidovudine/PHARMACOLOGY 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.
