Prediction of antifolate efficacy in a rat sarcoma model.
A methylcholanthrene-induced rat sarcoma propagated both in vitro and in vivo was used to examine the usefulness of a rapid biochemical in situ assay that measures thymidylate synthase (TS) activity in whole cells to predict sensitivity and resistance to the folate antagonists methotrexate (MTX), 10-ethyl-10-deazaaminopterin (10-EDAM) and trimetrexate (TMTX). There was an excellent correlation between the effects of these drugs on inhibiting TS and cytotoxicity as measured by a clonogenic assay, when the exposure time was 4 hr and those when the rat sarcoma cell line was employed (p less than 0.001). When tumor-cell suspensions were prepared from the rat sarcoma propagated in vivo, they were less sensitive to these antifolates, but the relative effectiveness of the 3 antifolates was similar: TMTX much greater than 10-EDAM greater than MTX. As expected, continuous exposure (10 to 12 days) produced cytotoxicity at a much lower dose of these drugs. When the 3 drugs were tested for anti-tumor effectiveness in rats bearing this tumor, the tumor regression measured was best with TMTX; 10-EDAM was intermediate in effectiveness as compared with MTX. These results indicate that the in situ TS assay and clonogenic assay may be used to predict anti-tumor efficacy of antifolates in vivo in this rat sarcoma.
Li
W W
WW
Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Lin
J T
JT
Chang
Y M
YM
Schweitzer
B
B
Bertino
J R
JR
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008748:Methylcholanthrene; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D013940:Thymidylate Synthase / Q000032:analysis*; D016597:Trimetrexate
D005493:Folic Acid Antagonists; D011799:Quinazolines; D008748:Methylcholanthrene; D013940:Thymidylate Synthase; C040210:edatrexate; D000630:Aminopterin; D016597:Trimetrexate; D008727:Methotrexate