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.