Cytotoxicity of tantalum(V) and niobium(V) small carborane complexes and mode of action in P388 lymphocytic leukemia cells (original) (raw)

2000, Applied Organometallic Chemistry

1. are potent cytotoxic agents against suspended tumors, producing cell death in several tissue culture lines; for example, all were effective against murine L1210 lymphoid leukemia, and all except 5 against murine P388 lymphocytic growth. Human leukemic growth is also retarded since 1-4 were effective against Tmolt 3 cell leukemia, all except 4 against Tmolt 4 leukemia, and 1, 2, and 5 against HI-60 leukemia. Cytotoxicity was found towards HuT-8 lymphoma, THP-1 acute monocytic leukemia and suspended HeLa-S 3 uterine carcinoma. Some but not all of the complexes were active against Sk-2 melanoma and Mcf-7 breast effusion growth. Mode-of-action studies in P388 lymphocytic leukemia cells showed that de novo purine synthesis was inhibited; this inhibition reduces DNA and RNA syntheses. Purine synthesis was reduced by compounds 3 and 4 at the regulatory enzymes, i.e. phosphoribosyl pyrophosphate (PRPP) amidotransferase and dihydrofolate reductase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The complexes afforded DNA fragmentation leading to apoptosis, but this was not by a mechanism of nucleoside alkylation, intercalation between base-pairs or cross-linking of the DNA strands.