metastat and Lung-Neoplasms

Matrix metalloproteinases (MMPs) play a significant role during the development and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess balance of MMPs. Established CaP cell lines that express high levels of MMPs frequently metastasize to the bone and the lungs. Drugs such as Taxol and alendronate that reduce cell motility and calcium metabolism reduce bony metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic inhibitors of MMPs that can be administered orally, including doxycycline (DC) and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat CaP model in vivo. Among several anti-MMP agents tested, CMT-3 (6-deoxy, 6-demethyl,4-de-dimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMT-3 and DC inhibited both the secretion and activity of MMPs by CaP cells. When tested for in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMT-3 and DC both reduced the lung metastases (> 50%). CMT-3, but not DC, inhibited tumor incidence (55 +/- 9%) and also reduced the tumor growth rate (27 +/- 9.3%). More significantly, the drugs showed minimum systemic toxicity. Ongoing studies indicate that CMT-3 may inhibit the skeletal metastases of CaP cells and delay the onset of paraplegia due to lumbar metastases. These preclinical studies provide the basis for clinical trials of CMT-3 for the treatment of metastatic disease.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Cell Survival; Doxycycline; Humans; Lung Neoplasms; Male; Metalloendopeptidases; Neoplasm Metastasis; Prostatic Neoplasms; Protease Inhibitors; Rats; Tetracyclines; Transplantation, Heterologous; Tumor Cells, Cultured

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] < or = 5.0 ,microg/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G(0)/G(1) compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 59.5 +/- 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Division; Dose-Response Relationship, Drug; Doxycycline; Hydroxyl Radical; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Transplantation; Prostatic Neoplasms; Protease Inhibitors; Rats; Tetracyclines; Tissue Inhibitor of Metalloproteinases; Tumor Cells, Cultured

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Division; Doxycycline; Drug Interactions; Epithelial Cells; Flurbiprofen; Humans; Lung Neoplasms; Male; Metalloendopeptidases; Neoplasm Metastasis; Prostatic Neoplasms; Protease Inhibitors; Rats; Regression Analysis; Tetracyclines; Tumor Cells, Cultured