Enhanced antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host toxicity with oral folic acid.
The purpose of this investigation was to determine whether antitumor selectivity of the third generation thymidylate synthase inhibitor 1843U89 could be enhanced by a combination of the drug with folic acid. The effects of folic acid on toxicity of 1843U89 to the dog and mouse and on antitumor efficacy of 1843U89 in the mouse were studied. These data were compared to the effect of folic acid on the in vitro cell culture antitumor activity of 1843U89. The sensitivity of eight cancer cell lines (three ovarian, one colon, one ileocecal, one epidermoid, one osteosarcoma, and one breast line) to 1843U89 was tested in vitro in the presence and absence of folic acid. Folic acid concentrations greater than 100 microM were required to decrease 1843U89 activity in seven of the cell lines. Only the activity in HCT-8, the ileocecal line, was reserved at folic acid concentrations below 100 microM. Oral folic acid given 30 min prior to an i.v. dose of 1843U89 increased the maximally tolerated dose and the lethal dose of 1843U89, both in dogs and in thymidine-depleted mice. In mice, oral folic acid produced little or no effect upon the antitumor efficacy of 1843U89 in two of three tumor cell lines in vivo. HCT-8, the line that was sensitive to folate reversal in vitro, was also sensitive in vivo. The results show that an oral dose of folic acid 30 min prior to i.v. 1843U89 can block mouse and dog intestinal toxicity without decreasing efficacy of 1843U89 in two of three human tumor lines in the nude mouse. Thus, the data reported here indicate that the antitumor selectivity of 1843U89 may be enhanced through a combination of 1843U89 with oral folic acid.
Division of Cell Biology, Wellcome Research Labs, Burroughs Wellcome, Research Triangle Park, North Carolina 27709, USA.
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Smith
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Amyx
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Boytos
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Duch
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Ferone
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Wilson
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005492:Folic Acid / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007410:Intestinal Diseases / Q000139:chemically induced; D054833:Isoindoles; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012516:Osteosarcoma / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007211:Indoles; D054833:Isoindoles; D011799:Quinazolines; C079601:1843U89; D005492:Folic Acid; D013940:Thymidylate Synthase; D002955:Leucovorin