A novel approach for improving the efficacy of experimental cancer chemotherapy using combinations of anticancer drugs and L-histidinol.
One of the major limitations to the chemical management of human malignancies is the failure of most antineoplastic agents to act specifically against tumour cells. A novel approach for improving both the specificity and the efficacy of experimental cancer chemotherapy is described in this review. The approach is based upon the use of L-histidinol in combination with conventional anticancer drugs. L-Histidinol, a structural analogue of the essential amino acid L-histidine, is a reversible inhibitor of protein biosynthesis which evokes disparate responses from non-tumorigenic and tumorigenic cells in culture. Whereas L-histidinol protects a wide variety of phenotypically normal cells from anticancer drug toxicity, it enhances the vulnerability of tumorigenic cells to the same agents. More importantly, these remarkable properties of L-histidinol are retained in tumour-bearing animals. Thus, L-histidinol diminishes the myelocytoxicity otherwise associated with the in vivo use of agents such as cytosine arabinoside and 5-fluorouracil. Simultaneously, L-histidinol increases the inherent capacities of these two antimetabolites to eradicate in situ tumour cells. More recently, it has been found that L-histidinol can increase both the specificity and the efficacy of a number of other antineoplastic agents. For example, alkylating agents such as BCNU, cyclophosphamide and cis-platinum, as well as the antitumour antibiotic daunomycin, can be combined with L-histidinol to provide curative treatment for tumour-bearing animals under conditions where these drugs, on their own, have little or no impact on survival. These results demonstrate that the L-histidinol/anticancer drug combination approach to chemotherapy is effective with a variety of clinically-relevant antineoplastic agents. However, it remains to be demonstrated whether this approach will prove applicable in, or effective for, human cancer chemotherapy.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002453:Cell Cycle / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity; D006641:Histidinol / Q000008:administration & dosage* / Q000633:toxicity; D007093:Imidazoles / Q000008:administration & dosage*; D007942:Leukemia, Experimental / Q000188:drug therapy; D012515:Mast-Cell Sarcoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*
D000970:Antineoplastic Agents; D007093:Imidazoles; D006641:Histidinol; D005472:Fluorouracil