Prediction of antifolate efficacy in a rat sarcoma model.

Abstract

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.

• Authors: W W Li, J T Lin, Y M Chang, B Schweitzer, J R Bertino
• Journal: International journal of cancer (Int J Cancer) Vol. 49 Issue 2 Pg. 234-8 (Sep 09 1991) ISSN: 0020-7136 [Print] United States
• PMID: 1831805 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Folic Acid Antagonists
• Quinazolines
• Methylcholanthrene
• Thymidylate Synthase
• edatrexate
• Aminopterin
• Trimetrexate
• Methotrexate

Topics

• Aminopterin (analogs & derivatives, therapeutic use)
• Animals
• Drug Screening Assays, Antitumor
• Folic Acid Antagonists (therapeutic use)
• Male
• Methotrexate (therapeutic use)
• Methylcholanthrene
• Quinazolines (therapeutic use)
• Rats
• Sarcoma, Experimental (chemically induced, drug therapy, enzymology)
• Thymidylate Synthase (analysis)
• Trimetrexate