methyl-3-5-diiodo-4-(4--methoxyphenoxy)benzoate and Breast-Neoplasms

Drug interaction between DIME or DIPE ¿1-[3, 5-diiodo-4-(4'-methoxyphenoxy)-phenyl]-ethanone¿ with vincristine and vinblastine on the growth rate of MDA-MB-231 human mammary cancer cells was determined by the median effect kinetic method. Mutually exclusive cellular binding sites were identified kinetically and isobologram analyses showed potentiation. The combind effect of 0.75 MICROM DIME and 2 nM vincristine demonstrated a nearly type of mutual activation. It was shown that the nonhydrolyzable DIME derivative DIPE is equivalent to DIME, but because of its biological stability is a preferred drug candidate. Vinblastine-DIME cooperative action is similar to that of vincristine-DIME (or DIPE). Activation of caspase 3 by both DIME and vincristine is greatly potentiated when both drugs are added simultaneously in a given proportion. We propose that following a primary binding of DIME and vinca alkaloids to microtubules, an as yet unrecognized mutual activation of caspase 3 apoptotic path is initiated, explaining DNA fragmentation and cell death. A subpopulation of cancer cells, capable of slow growth at 1.5 microM DIME was identified. This cell type was also killed by the DIME-vincristine drug combination.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Caspase 3; Caspases; Cell Death; Cysteine Endopeptidases; DNA Damage; DNA Fragmentation; Drug Synergism; Female; Humans; Iodobenzenes; Iodobenzoates; Kinetics; Phenyl Ethers; Tumor Cells, Cultured; Vinblastine; Vincristine

We identified a structural analog of thyroid hormone, methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (Oncocidin A1), that inhibits human carcinoma cell proliferation and the growth of human breast (MDA MB-231) and ovarian (OVCAR-3) carcinoma xenografts in nude mice. This novel antitumor agent is orally bioavailable and well tolerated by animals. Exposure of MCF-7 and MDA MB-231 breast carcinoma cells to Oncocidin A1 in vitro caused a cell-cycle arrest in prometaphase (a G2/M arrest) and apoptosis, suggesting a cytotoxic mechanism involving mitotic spindle function. The interaction of Oncocidin A1 with microtubules was demonstrated by: 1) immunofluorescence studies of microtubule assembly in the presence of the drug in cell-free and in cellular assays; and 2) in vitro binding inhibition studies involving radiolabeled Oncocidin A1 or colchicine and tubulin monomers. Taken together, these experiments indicate that Oncocidin A1 perturbs cellular microtubule assembly, possibly by binding to the colchicine site on tubulin. Three-dimensional structural modelling of Oncocidin A1 revealed that it can adopt a twisted conformation similar to that of combretastatin A-4, which binds to the colchicine site of tubulin. The novel structural features of Oncocidin A1 could guide the design of a new class of microtubule-binding antitumor agents having substantially reduced normal tissue toxicity upon oral administration.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Cell Division; Female; Humans; Iodobenzoates; Metaphase; Mice; Mice, Nude; Mitosis; Neoplasm Transplantation; Ovarian Neoplasms; Phenyl Ethers; Protein Binding; Transplantation, Heterologous; Tubulin