Methotrexate (MTX) Concentration in Tumors Following Low-dose MTX

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1987 Jan 1

PMID 2441884

Citations 2

Authors

N J Winick

B A Kamen

A Streckfuss

J Craig

F McGuirt

R L CAPIZZI

F Sklar

D COLN

Affiliations

Soon will be listed here.

Abstract

Methotrexate (MTX) is a folate analog competitive with reduced folates for cellular transport and metabolism. Since the normal plasma folate concentration is only 10(-8) M, we tested the possibility that there may be a saturable uptake of MTX by proliferating tumor tissue at plasma MTX concentrations of only 10(-7) to 10(-6) M. Patients with advanced malignancies, refractory to accepted therapy, were given low-dose oral MTX (30-60 mg/m2 total dose in four to eight divided doses). Tumor tissue was biopsied 18-24 h after the last oral dose of MTX. The concentrations of MTX and its polyglutamated derivatives were measured in these samples. Forty-eight percent of the drug in the tumor samples was present as a polyglutamated derivative.

Citing Articles

Treatment of the rat R-1 rhabdomyosarcoma with methotrexate and radiation; effects of timing on cell survival and tumour growth delay.

Kipp J, Kal H, van Gennip A, van Berkel A J Cancer Res Clin Oncol. 1993; 119(4):215-20.

PMID: 8423196 DOI: 10.1007/BF01624433.

Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study.

Graham M, Shuster J, Kamen B, Cheo D, Harrison M, Leventhal B Cancer Chemother Pharmacol. 1992; 31(3):217-22.

PMID: 1464159 DOI: 10.1007/BF00685551.

References

Whitehead V, Perrault M, Stelcner S . Tissue-specific synthesis of methotrexate polyglutamates in the rat. Cancer Res. 1975; 35(11 Pt 1):2985-90. View

Curt G, Jolivet J, Carney D, Bailey B, Drake J, Clendeninn N . Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate. J Clin Invest. 1985; 76(4):1323-9. PMC: 424067. DOI: 10.1172/JCI112106. View

Keefe D, CAPIZZI R, Rudnick S . Methotrexate cytotoxicity for L5178Y/Asn- lymphoblasts: relationship of dose and duration of exposure to tumor cell viability. Cancer Res. 1982; 42(5):1641-5. View

Jolivet J, Schilsky R . High-pressure liquid chromatography analysis of methotrexate polyglutamates in cultured human breast cancer cells. Biochem Pharmacol. 1981; 30(11):1387-90. DOI: 10.1016/0006-2952(81)90330-0. View

Kirkwood J, Canellos G, Ervin T, Pitman S, Weichselbaum R, Miller D . Increased therapeutic index using moderate dose methotrexate and leucovorin twice weekly vs. weekly high dose methotrexate-leucovorin in patients with advanced squamous carcinoma of the head and neck: a safe new effective regimen. Cancer. 1981; 47(10):2414-21. DOI: 10.1002/1097-0142(19810515)47:10<2414::aid-cncr2820471016>3.0.co;2-w. View

Poser R, Sirotnak F, Chello P . Differential synthesis of methotrexate polyglutamates in normal proliferative and neoplastic mouse tissues in vivo. Cancer Res. 1981; 41(11 Pt 1):4441-6. View

Kamen B, Takach P, Vatev R, CASTON J . A rapid, radiochemical-ligand binding assay for methotrexate. Anal Biochem. 1976; 70(1):54-63. DOI: 10.1016/s0003-2697(76)80047-4. View

Krakower G, Kamen B . In situ methotrexate polyglutamate formation in rat tissues. J Pharmacol Exp Ther. 1983; 227(3):633-8. View

Antony A, Kane M, Portillo R, Elwood P, Kolhouse J . Studies of the role of a particulate folate-binding protein in the uptake of 5-methyltetrahydrofolate by cultured human KB cells. J Biol Chem. 1985; 260(28):14911-7. View

10.

DeConti R, Schoenfeld D . A randomized prospective comparison of intermittent methotrexate, methotrexate with leucovorin, and a methotrexate combination in head and neck cancer. Cancer. 1981; 48(5):1061-72. DOI: 10.1002/1097-0142(19810901)48:5<1061::aid-cncr2820480502>3.0.co;2-x. View

11.

Samuels L, Feinberg A, Moccio D, Sirotnak F, Rosen G . Detection by high-performance liquid chromatography of methotrexate and its metabolites in tumor tissue from osteosarcoma patients treated with high-dose methotrexate/leucovorin rescue. Biochem Pharmacol. 1984; 33(17):2711-4. DOI: 10.1016/0006-2952(84)90685-3. View

12.

Kamen B, Capdevila A . Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci U S A. 1986; 83(16):5983-7. PMC: 386421. DOI: 10.1073/pnas.83.16.5983. View

13.

Goldin A, Mantel N, GREENHOUSE S, Venditti J, HUMPHREYS S . Effect of delayed administration of citrovorum factor on the antileukemic effectiveness of aminopterin in mice. Cancer Res. 1954; 14(1):43-8. View

14.

Djerassi I, Farber S, ABIR E, Neikirk W . Continuous infusion of methotrexate in children with acute leukemia. Cancer. 1967; 20(2):233-42. DOI: 10.1002/1097-0142(1967)20:2<233::aid-cncr2820200209>3.0.co;2-8. View

15.

Taylor 4th S, McGuire W, Hauck W, Showel J, Lad T . A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer. J Clin Oncol. 1984; 2(9):1006-11. DOI: 10.1200/JCO.1984.2.9.1006. View

16.

Kamen B, Winick N . Analysis of methotrexate polyglutamate derivatives in vivo. Methods Enzymol. 1986; 122:339-46. DOI: 10.1016/0076-6879(86)22191-6. View

17.

Djerassi I, ROMINGER C, Kim J, Turchi J, Suvansri U, Hughes D . Phase I study of high doses of methotrexate with citrovorum factor in patients with lung cancer. Cancer. 1972; 30(1):22-30. DOI: 10.1002/1097-0142(197207)30:1<22::aid-cncr2820300105>3.0.co;2-b. View