Protection of cells from methotrexate toxicity by 7-hydroxymethotrexate

Abstract

Summary Cell growth survival studies have revealed that 7-OH methotrexate is two orders of magnitude less cytotoxic to human melanoma and human acute lymphoblastic leukaemia (ALL) cells in vitro than methotrexate. The influence of 7-OH methotrexate on methotrexate toxicity was investigated by studying cell growth in the presence of methotrexate and its 7-OH metabolite and by studying [3H] In a previous study it was shown that two factors may contribute to the continued survival of tumour cells in vivo from the effects of high-dose methotrexate therapy with leucovorin rescue. These two factors were: 1. The concentration of 7-OH methotrexate in plasma which may be sufficient to inhibit the further uptake of methotrexate. 2. The rescue agent leucovorin which may salvage both host tissue and viable tumour cells from the toxic effects of methotrexate.This study reports on the role that the 7-OH metabolite of methotrexate may have in affording protection to tumour cells against methotrexate. To date this aspect of methotrexate therapy has received limited attention (Lankelma et al., 1980) and the major concern for this metabolite is for its role in renal toxicity during high dose therapy (Jacobs et al., 1976).The effect of methotrexate on the toxicity to human melanoma and human acute lymphoblastic leukaemia (ALL) cells in the presence of 7-OH methotrexate was investigated. A companson was made of the melanoma cell lines ADLER, B8 and BlO with the ALL cell line KM3, which was reported to be methotrexate sensitive in vivo (Schnieder et al., 1977

Pharmacokinetic Profile of Methotrexate and 5-Fluorouracil in Normal and Bilharzial-infested Mice

“…This may be due to partial liver impairment induced by bilharzial infestation, for liver was found to be the major site of de toxification of MTX [20]. Moreover, it is worth mentioning that the 7-OH derivative of MTX, a metabolic product of MTX, may limit MTX toxicity [21] to dividing cells by interfering with MTX uptake [22] and polyglutamylation [23,24]. That is why the delay in the conversion of MTX to 7-OH-MTX may be the cause of the unexpected toxicity observed in Egyptian can cer patients with a previous history of bilharziasis [Gad-El-Mawla, pers.…”

Distribution of 7-hydroxymethotrexate in human blood

“…Because of an aqueous solubility 3 to 5-fold less than MTX, the 7-hydroxy metabolite has been proposed as a mediator of renal toxicity following high-dose MTX treatment (Jacobs et a1 1976(Jacobs et a1 , 1977. 7-OH-MTX has further been demonstrated to inhibit influx, reduce polyglutamation, and enhance efflux of MTX in-vitro (Lankelma et a1 1980;Fabre et a1 1983a, b;Gaukroger & Wilson 1984;McGuire et a1 1984). Depending on its distribution in man, 7-OH-MTX might thus modify target cell response and the clinical outcome of high-dose MTX therapy in several ways.…”

Pharmacokinetic Drug Interactions with Anticancer Drugs

“…The correlation between plasma drug concentrations and systemic toxicity of methotrexate was established some time ago Stroller et al 1977) and calcium folinate (leucovorin calcium) is routinely used as a rescue agent to reverse this toxicity. Methotrexate undergoes hepatic metabolism to 7-hydroxymethotrexate, which is reported to be far less cytotoxic in vitro than methotrexate (Gaukroger & Wilson 1984).…”