SYNTHESIS AND CYTOTOXIC ACTION OF 3,5-ISOXAZOLIDINEDIONES AND 2-ISOXAZOLIN-5-ONES IN MURINE AND HUMAN TUMORS

The 3,5-isoxazolidmediones and 2-isoxazonn-3-ones demonstrated potent cytotoxicity against the growth of human Tmolt(3) T cell leukemia, mur ine P388 and L1210 leukemias as well as human HeLa-S-3 uterine carcino ma and glioma tumor cell growth. The specificity of the 3,5-isoxazolid inedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varie d with the histological type of tumor cell, Selected compounds were ac tive against solid HeLa uterine, KB nasopharynx, skin A431, SW-480 ade nocarcinoma, osteosarcoma and glioma growth. Selected compounds demons trated in vivo antineoplastic activity against Ehrlich ascites carcino ma growth. In L-1210 leukemia cells, the agents blocked DNA and protei n synthesis at 25, 50 and 100 mu M over 60 min The agents were effecti ve in reducing rate limiting enzymes in the de novo purine and pyrimid ine pathways, In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA an d RNA polymerase activities, DNA itself was not a target of the agents .