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An Innovative Strategy for the Prevention and Treatment of Metastatic Prostate Cancer: Modified Tetracyclines as Chemotherapeutics

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Annual rept. 1 Oct 1998-30 Sep 1999

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During the period 100198-093099, we investigated the effects of a novel anti-metastatic drug, CMT-3, on prostate cancer cells in vitro and in vivo. We focused on three main areas 1 Inhibition of metastases in the Dunning MAT LyLu rat model. Bone and lung metastases were induced in male Copenhagen rats by intravenous injection of tumor cells as per Geldof and Rao. Daily oral administration of CMT-3 began at 7 or 2 days prior or 1 day following implant. CMT-3 treated rats had a significant delay in development of pulmonary morbidity and a subsequent increase in survival which correlated with the predosing period. Paraplegia developed in 83-90 of controls, but was only 10-30 in all treatment groups. These results verify the potential of CMT-3 for use in human skeletal metastasis. 2 Mechanism of CMT-3-induced programmed cell death PCD. Studies revealed that CMT-3 induces PCD by inhibiting mitochondrial function suppression of bcl-2 and bcix proteinselevation of bax and inducing hydroxyl radicals rapid activation of caspase-1 and 3 in vivo and in vitro. 3 Influence of stromal cells on the cytotoxicity of antitumor drugs on prostate cancer cells in vitro. Organ specific stromal cells isolated from bone marrow and lung, but not dermal fibroblasts, inhibited the cytologic effects of CMT-3, doxyrubicin and taxol. This was partially reversed by treatment with hyaluronidase.

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  • Medicine and Medical Research

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