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This report appraises the efficacy of doxycycline (DC) and non\u2010antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation <jats:italic>in vitro<\/jats:italic>. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6\u2010deoxy, 6\u2010demethyl, 4\u2010de\u2010dimethylamino tetracycline (CMT\u20103, COL\u20103), was the most potent inhibitor (50% inhibition dose [GI<jats:sub>50<\/jats:sub>] \u2264 5.0 \u03bcg\/ml). Exposure of tumor cells to CMT\u20103 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT\u20103. Cell cycle arrest at the G<jats:sub>0<\/jats:sub>\/G<jats:sub>1<\/jats:sub> compartment was observed in CMT\u20103\u2010 and DC\u2010treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells <jats:italic>in vitro<\/jats:italic>, from 10% (CMT\u20106) to &gt;90% (CMT\u20103). CMT\u20103 and DC decreased matrix metalloproteinase (MMP)\u20102, tissue inhibitor of MMP (TIMP)\u20101 and TIMP\u20102 secretion in treated cultures and inhibited activity of secreted MMPs, CMT\u20103 was a stronger inhibitor. Daily oral gavage of DC and CMT\u20103 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27\u201335%) and lung metastases were observed (28.9 \u00b1 15.4 sites\/animal [CMT\u20103\u2010treated] <jats:italic>versus<\/jats:italic> 43.6 \u00b1 18.8 sites\/animal [DC\u2010treated] <jats:italic>versus<\/jats:italic> 59.5 \u00b1 13.9 [control]; <jats:italic>p<\/jats:italic> &lt; 0.01]. A delay in tumor growth (27 \u00b1 9.3%, <jats:italic>p<\/jats:italic> &lt; 0.05), reduction in metastases (58 \u00b1 8%) and decrease in tumor incidences (55 \u00b1 9%, CMT\u20103\u2010treated) were also observed, when rats were predosed for 7 days. No significant drug\u2010induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT\u20103 as an oral, nontoxic drug to treat metastatic prostate and other cancers. \u00a9 2001 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.10168","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T04:51:41Z","timestamp":1030251101000},"page":"297-309","source":"Crossref","is-referenced-by-count":129,"title":["Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non\u2010antimicrobial tetracycline analog (COL\u20103) in a metastatic prostate cancer model"],"prefix":"10.1002","volume":"98","author":[{"given":"Bal L.","family":"Lokeshwar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie 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