L-Histidinol attenuates Fanconi syndrome induced by ifosfamide in rats.

The effect of L-histidinol (LHL), a structural analogue of the essential amino acid L-histidine, on ifosfamide (IFO) induced nephrotoxicity was investigated in the rat. The aim of this study was to assess whether oral supplementation of LHL could attenuate Fanconi syndrome (FS) induced by IFO. Male Wistar albino rats received daily injections of IFO (50 mg/kg) for 5 days with or without oral supplementation of 0.5% LHL in the drinking water. LHL was supplemented for 3 days before IFO administration and daily thereafter. Control rats were injected with saline with or without oral LHL. The results demonstrated that IFO induces a FS characterized by wasting of glucose, electrolytes, and organic acids, along with elevated serum creatinine and urea levels and decreased creatinine clearance. IFO-induced FS was associated with significant renal nonprotein sulfhydryl depletion and lipid peroxide (malondialdehyde) accumulation. LHL strongly ameliorated the severity of renal dysfunction induced by IFO, with significant decreases in total and fractional excretions of Na(+), K(+), PO(4)(3-), and glucose. Also, LHL significantly decreased the elevated serum creatinine and urea levels and significantly increased the creatinine clearance. Moreover, the beneficial effects of LHL were associated with a significant improvement of IFO-induced nonprotein sufhydry depletion and lipid peroxide accumulation. These results demonstrate that oral supplementation of LHL can partially protect against IFO-induced FS in rats.

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.

Enhancement of anticancer agent activity by selective inhibition of rapidly proliferating tissues of the host.

Most cytotoxic drugs used in cancer therapy do not discriminate between neoplastic and normal proliferating cells. To avoid irreversible damage to vital host tissues, such as bone marrow and intestine, drugs must be administered at dosages which usually prove insufficient to eradicate all of the neoplastic cells present. This review focuses on an approach to improve cancer chemotherapy by selectively protecting normal, proliferating cells during treatment, thereby permitting the administration of otherwise lethal doses of drug. Preclinical in vivo studies of cytokinetic modulation with interferon, or L-histidinol, as well as recent clinical studies of interferon modulation of the activity of 5-fluorouracil are reviewed.

Chemotherapeutic activity of L-histidinol against spontaneous, autochthonous murine breast tumors.

In experiments designed to investigate the biochemical basis for the diminution of the antitumor activity of 5-fluorouracil (FUra) by L-histidinol in CD8FI breast tumors, it was discovered that L-histidinol inhibits RNA and DNA synthesis in these tumors. This finding suggested the possibility that L-histidinol might have antiproliferative activity in the CD8FI breast tumor, and on that basis we evaluated different administration schedules of L-histidinol for antitumor activity in vivo. The present report describes a schedule of L-histidinol administration which yielded significant activity against spontaneous, autochthonous CD8FI breast tumors consistently at tolerable doses. To our knowledge, there are no previous reports of in vivo antitumor activity associated with the administration of L-histidinol as a single agent.