Role of oncogenes in resistance and killing by cancer therapeutic agents.
Chemotherapeutic drug resistance is a major clinical problem and cause for failure in the therapy of human cancer. One of the goals of molecular oncology is to identify the underlying mechanisms, with the hope that more effective therapies can be developed. Several mechanisms have been suggested to contribute to chemoresistance: 1) amplification or overexpression of the P-glycoprotein family of membrane transporters (eg, MDR1, MRP, LRP) which decrease the intracellular accumulation of chemotherapy; 2) changes in cellular proteins involved in detoxification (eg, glutathione S-transferase pi, metallothioneins, human MutT homologue, bleomycin hydrolase, dihydrofolate reductase) or activation of the chemotherapeutic drugs (DT-diaphorase, nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase); 3) changes in molecules involved in DNA repair (eg, O6-methylguanine-DNA methyltransferase, DNA topoisomerase II, hMLH1, p21WAF1/CIP1; 4) activation of oncogenes such as Her-2/neu, bcl-2, bcl-XL, c-myc, ras, c-jun, c-fos, MDM2, p210 BCR-abl, or mutant p53. An overview of these resistance mechanisms is presented, with a particular focus on the role of oncogenes. Some current strategies attempting to reverse their effects are discussed.
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Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D017209:Apoptosis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000502:physiology; D006801:Humans; D006867:Hydrolases / Q000502:physiology; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000502:physiology; D008297:Male; D008668:Metallothionein / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D009857:Oncogenes; D010088:Oxidoreductases / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007527:Isoenzymes; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D008668:Metallothionein; D010088:Oxidoreductases; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D006867:Hydrolases