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.