Effective treatments for controlling prostate cancer metastasis are not yet available. Investigations of this and other metastatic cancers have revealed stromal-induced factors that confer """"""""acquired drug resistance"""""""". In prostate cancer, stromal factors induce pro-inflammatory cytokines, IL-1beta, IL-6 and IL-8 production in tumor cells. This coincides with increased resistance to cytotoxic/anti-metastatic drugs, such as doxorubicin, and CMT-3 (a novel cytotoxic and anti-metastatic tetracycline analog). Blocking IL-1beta and IL-6 production by antisense cDNA transfection sensitizes tumor cells to chemodrugs, whereas, blocking IL-8 production decreases their invasive potential. A combination of cytotoxic and anti-inflammatory drugs reduces the expression of these cytokines. Thus, a combination therapy that inhibits cytokine production during an inflammatory response to chemotherapy should improve the efficacy of cytotoxic and anti-metastatic drugs. The goals of this proposal are: 1. To establish a cause and effect relationship between tumor cell-associated cytokine production and acquired drug resistance, as well as, tumor progression. (2) Evaluate the efficacy of combined cytotoxic and anti-inflammatory drugs to control metastatic prostate cancer. A cause-effect relationship between cytokine production and tumor progression will be established by investigating, in xenografts, the growth and metastasis of prostate cancer cells (PC-3ML and LNCaP), expressing green fluorescence protein and cDNA -sense and anti-sense constructs of IL-1beta, IL-6 or IL-8. Possible interlinked roles of these 3 cytokines will be investigated by characterizing double transfectants of PC-3ML expressing IL-1beta antisense/IL-6sense and IL-1beta sense/IL-8antisense cDNAs (Aim 1). Alterations in drug-induced cytotoxicity in PC-3ML and LNCaP transfectants, selectively altered in cytokine production, will be studied by cytotoxicity assays, cDNA microarray analysis, followed by RT-PCR and protein ELISAs. Drug-induced changes in stromal factors responsible for altering drug sensitivity will also be examined (Aim 2). The efficacy of a combination of a cytotoxic/anti-metastatic drug (i.e., CMT-3) and an anti-inflammatory drug (i.e., Celecoxib) will be tested in PC-3ML and LNCaP cytokine transfectants in xenografts.
(Aim 3). The proposed study should reveal the role of cytokines in acquired drug resistance and prostate cancer progression. It will also establish whether a combined cytotoxic and anti-inflammatory therapy will be more effective in controlling metastatic prostate cancer.
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