Agents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer

Kelloff, Gary J.; Lieberman, Ronald; Steele, Vernon E.; Boone, Charles W.; Lubet, Ronald A.; Kopelovich, Levy; Malone, Winfred A.; Crowell, James A.; Higley, Howard R.; Sigman, Caroline C.

doi:10.1016/s0090-4295(00)00940-7

Cited by 59 publications

(41 citation statements)

References 17 publications

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“…Note that amphipathic-L did not inhibit PSA synthesis, suggesting that the reduction in the PSA level was probably due to the reduction in tumor size. Therefore, prolonged treatment with amphipathic-D is not likely to interfere with the validity of PSA as an indicator of prostate carcinoma progression, in contrast to other drugs, such as antiandrogen or antiestrogen chemotherapeutics (42).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Papo

Braunstein²,

Eshhar³

et al. 2004

Cancer Research

112

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Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D-and L-amino acids (diastereomer), which targets both androgen-independent and androgendependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all L-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.

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Section: Discussionmentioning

confidence: 99%

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Papo

Braunstein²,

Eshhar³

et al. 2004

Cancer Research

112

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“…Since almost all rat mammary tumors are estrogen dependent, these tumors generally respond to agents that interrupt estrogensignaling pathways (Nandi et al, 1995). However, estrogen is not the only factor that affects human breast cancer development (Kelloff et al, 1998). Unlike rat mammary tumors and like a significant portion of human breast cancer, mouse mammary tumors are less estrogen dependent.…”

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confidence: 99%

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Ren

Tilli

et al. 2003

Oncogene

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Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dosedependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P ¼ 0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P ¼ 0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P ¼ 0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.

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“…One possible explanation for the discrepancy between the results obtained in animal studies and the results of pilot clinical trials may be related to the insufficient dose used in humans (44,58). In vitro, the induction of apoptosis by 4-HPR is evident at higher concentrations than those achieved in vivo at the oral dose 200 mg/d (12).…”

Section: Discussionmentioning

confidence: 99%

Effect of the Synthetic Retinoid Fenretinide on Circulating Free Prostate-Specific Antigen, Insulin-Like Growth Factor-I, and Insulin-Like Growth Factor Binding Protein-3 Levels in Men with Superficial Bladder Cancer

Serrano¹,

Baglietto²,

Johansson³

et al. 2005

Clinical Cancer Research

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Purpose: Fenretinide (4-HPR) is a synthetic retinoid that has shown a preventive activity in prostate cancer animal models.Experimental Design: We measured the changes in total and free prostate-specific antigen (PSA) and its association with insulin-like growth factor I (IGF-I) and IGFBP-3 levels after 1 year of treatment in 24 subjects given 4-HPR and 24 control subjects enrolled in a randomized bladder cancer prevention trial.Results: No significant effect of 4-HPR was observed on total and free fraction of PSA levels. The median percentage [95 confidence interval (95% CI)] change for % free PSA and total PSA in the 4-HPR and the control group were, respectively, 7.6 (95% CI, À À4.0 to 69.3) versus 5.1 (95% CI, À À21.4 to 59.8) and À À7.8 (95% CI, À À18.2 to 52.5) versus À À12.3 (95% CI, À À44.6 to 9.6). However, in patients ages <60 years, there was a trend to an increase of total free PSA and % free PSA after treatment with 4-HPR that was different from a trend to a decrease in the control group (P = 0.002 and 0.052, respectively). The interaction between age and treatment was statistically significant on free PSA (P = 0.001). A similar pattern was noted with smoking status (P = 0.011 for the interaction on free PSA). No association was observed between PSA levels and IGF-I or IGFBP-3 levels. Conclusions:We conclude that 4-HPR has no significant effect on circulating PSA, but it increases significantly free PSA levels in subjects younger than 60 years and in nonsmokers. These effects might support an activity in prostate cancer prevention but further studies are required.

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Agents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer

Cited by 59 publications

References 17 publications

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Effect of the Synthetic Retinoid Fenretinide on Circulating Free Prostate-Specific Antigen, Insulin-Like Growth Factor-I, and Insulin-Like Growth Factor Binding Protein-3 Levels in Men with Superficial Bladder Cancer

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