13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti-prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.
Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone-releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.
Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P =.12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).
Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.
[Show abstract][Hide abstract] ABSTRACT: This project is a study of the potential role of retinoic acid receptor in the metastasis of prostate cancer. Using prostate cancer cell lines, we found that the RXR-alpha expression was highly correlated with retinoid sensitivity. Clinical samples showed a trend towards a decreased expression in metastatic cells compared to the primary tumor cells. To determine whether the retinoid receptor RXR-alpha was directly involved in determining retinoid sensitivity, we prepared an adenovirus transducing RXR-alpha was created. Cancer cell lines were transduced with the adenovirus to overexpress the gene. These RXR-alpha transduced cells were showed no change in the sensitivity to retinoids in vitro. In addition we developed an experimental model of prostate cancer bone metastasis in nude mice. In this model, the transduction of the RXR-alpha by the adenovirus vector had no effect on bone metastasis. We conclude that in the experimental systems used, RXR-alpha is a marker of retinoid sensitivity but does not confer retinoid sensitivity or alter metastatic potential.
[Show abstract][Hide abstract] ABSTRACT: Retinoid derivatives have been of special interest in cancer research because of their antiproliferative and differentiation-inducing activities in premalignant and malignant cells. Some retinoids are clinically effective in cancer therapy and prevention, and all-trans-retinoic acid is being used for the treatment of acute promyelocytic leukemia. Unfortunately, classical retinoids are not effective against most advanced solid tumors and cause undesirable side effects, which have limited the full development of retinoids as chemopreventive and chemotherapeutic drugs. The recent identification of selective retinoid derivatives capable of inducing apoptosis and their combination with other anticancer therapies promises a more effective and less toxic manner to the successful use of retinoids in cancer therapy.
Drug Resistance Updates 06/2002; 5(3-4):162-75. DOI:10.1016/S1368-7646(02)00050-X · 9.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given their novel mechanisms of action and relatively favorable toxicity profiles, differentiation agents have been the focus of much investigation in the field of oncology. Among the most well studied of these agents in prostate cancer have been the retinoids, vitamin D, peroxisome-proliferator-activated receptor gamma (PPARgamma) ligands, and, most recently, the histone deacetylase (HDAC) inhibitors. While the clinical activity of these agents has been limited, several obstacles to the development of these novel drugs have become apparent. A lack of validated measures of outcome and uncertainty regarding the appropriate disease states in which to test these agents have led to difficulty in trial design. Furthermore, a better understanding of the biologic targets and genes manipulated by these therapies is required such that more potent and selective drugs may be developed. By overcoming these obstacles, the full potential of this therapeutic class may be realized.
Seminars in Oncology 10/2003; 30(5):689-97. DOI:10.1016/S0093-7754(03)00355-5 · 3.90 Impact Factor
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