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Table of Contents
Vol. 14, Suppl. 1, 2005
Issue release date: July 2005
Section title: Review

Open Access Gateway

Med Princ Pract 2005;14:35–48

Mechanisms of Drug Resistance in Cancer Chemotherapy

Luqmani Y.A.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait
email Corresponding Author

Prof. Y.A. Luqmani

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University

PO Box 24923

13110 Safat (Kuwait)

Tel. +965 533 7135, Fax +965 5342807, E-Mail yunus@hsc.edu.kw

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The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.

© 2005 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Review

Received: April 18, 2002
Accepted: February 19, 2005
Published online: July 09, 2008
Issue release date: July 2005

Number of Print Pages: 14
Number of Figures: 1
Number of Tables: 3

ISSN: 1011-7571 (Print)
eISSN: 1423-0151 (Online)

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