L-histidinol in experimental cancer chemotherapy: improving the selectivity and efficacy of anticancer drugs, eliminating metastatic disease and reversing the multidrug-resistant phenotype.
Human cancer chemotherapy is limited by two major problems: the failure of commonly used anticancer drugs to act against tumor cells in a specific manner and the ability of malignant cells to resist killing by antineoplastic agents. Experimentally, both of these problems can be solved by using L-histidinol in combination with conventional anticancer drugs. A structural analogue of the essential amino acid L-histidine and an inhibitor of protein biosynthesis. L-histidinol improves the selectivity and the efficacy of a variety of cancer drugs in several transplantable murine tumors. Furthermore, L-histidinol circumvents the drug-resistant traits of a variety of cancer cells, including those showing multidrug resistance. This review will summarize these properties of L-histidinol, present new evidence on its ability to increase the vulnerability of both drug-sensitive and drug-resistant human leukemia cells to various anticancer drugs, and show that, in addition to inhibiting protein synthesis, L-histidinol acts as an intracellular histamine antagonist. The establishment of a connection between the latter mechanism and the capacity to modulate anticancer drug action has resulted in a clinical trial in the treatment of human cancer.
Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
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Warrington
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D004351:Drug Resistance; D006633:Histamine Antagonists / Q000494:pharmacology; D006643:Histidine-tRNA Ligase / Q000037:antagonists & inhibitors*; D006641:Histidinol / Q000494:pharmacology / Q000627:therapeutic use*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006633:Histamine Antagonists; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010714:Phosphatidylethanolamines; C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D006641:Histidinol; D006643:Histidine-tRNA Ligase