A phase II trial of all- trans -retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis

Trump, Donald L.; Smith, David C.; Stiff, Dwight D.; Adedoyin, Adedayo; Day, Roger; Bahnson, Robert R.; Hofacker, Janie; Branch, Robert A.

doi:10.1007/s002800050582

Cited by 58 publications

(41 citation statements)

References 23 publications

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“…Retinoids have been shown to inhibit prostate cancer growth both in cell culture (43)(44)(45)(46) and in animal models (43,(47)(48)(49). Clinical trials using retinoids in the treatment of prostate cancer have thus far shown only modest efficacy (50)(51)(52). Our findings implicate ALDH1a2 as a tumor suppressor gene in prostate cancer and provide rationale for further investigating retinoids for the prevention or treatment of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Kim¹,

Lapointe

Kaygusuz³

et al. 2005

Cancer Research

123

110

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Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2V-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1a2), was also associated with shorter recurrence-free survival. ALDH1a2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1a2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1a2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1a2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1a2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer. (Cancer Res 2005; 65(18): 8118-24)

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Section: Discussionmentioning

confidence: 99%

The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Kim¹,

Lapointe

Kaygusuz³

et al. 2005

Cancer Research

123

110

View full text Add to dashboard Cite

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“…Because ATRA is a hydrophobic drug and to prevent its rapid clearance due to enhanced metabolism, we used liposomes to deliver the drug (39). L-ATRA, the liposomal form of ATRA, was prepared in bottles from lyophilized powder in bottles containing ATRA (100 mg) in a 1:15 drug:lipid formulation that consisted of soy oil and dimyristoylphosphatidylcholine (kindly supplied by Aronex Pharmaceuticals, Inc., The Woodlands, TX, as Atragen R ).…”

Section: Methodsmentioning

confidence: 99%

Par-4 Transcriptionally Regulates Bcl-2 through a WT1-binding Site on the bcl-2 Promoter

Cheema

Mishra

Rangnekar

et al. 2003

Journal of Biological Chemistry

119

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Elevated expression levels of the bcl-2 proto-oncogene have been extensively correlated with the appearance of androgen independence in prostate cancer. Although bcl-2 was first cloned as the t(14:18) translocation breakpoint from human follicular B cell lymphoma, the mechanism of overexpression of bcl-2 is largely undefined for advanced prostate cancer because there are no gross alterations in the gene structure. We investigated the role of the product of the prostate apoptosis response gene-4 (Par-4) and the product of the Wilms' tumor 1 gene (WT1) in the regulation of Bcl-2 expression in prostate cancer cell lines. We observed growth arrest and apoptosis, upon decreasing Bcl-2 protein and transcript in the high Bcl-2-expressing, androgen-independent prostate cancer cell line, by all-trans-retinoic acid treatment (ATRA), but this did not occur in the androgen-dependent cell line expressing low levels of Bcl-2. The decrease in the Bcl-2 protein and transcript following all-trans-retinoic acid treatment was accompanied by changes in localization of Par-4 and an induction in the expression of WT1 protein. In stable clones expressing ectopic Par-4 and in ATRA-treated cells, we observed decreased Bcl-2 protein and transcript. This was accompanied by an induction in WT1 expression. The involvement of WT1 in the Par-4-mediated down-modulation of Bcl-2 was further defined by blocking endogenous WT1 expression, which resulted in an increase in Bcl-2 expression. Finally, we detected Par-4 and WT1 proteins binding to a previously identified WT1-binding site on the bcl-2 promoter both in vitro and in vivo leading to a decrease in transcription from the bcl-2 promoter. We conclude that Par-4 regulates Bcl-2 through a WT1-binding site on the bcl-2 promoter. These data also identify Par-4 nuclear localization as a novel mechanism for ATRA-mediated bcl-2 regulation.

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“…Differences in ATRA and 13-cis-RA metabolism and pharmacokinetics have been reported in cancer patients [24][25][26][27][28][29][30]. ATRA is rapidly cleared from plasma (plasma half-life <1 h) and induces its own metabolism, which is a significant therapeutic obstacle.…”

Section: Retinoic Acid Receptorsmentioning

confidence: 99%

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Labeur

Paez-Pereda²,

Arzt

et al. 2008

Rev Endocr Metab Disord

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Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing's disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing's disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

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A phase II trial of all- trans -retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis

Cited by 58 publications

References 23 publications

The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Par-4 Transcriptionally Regulates Bcl-2 through a WT1-binding Site on the bcl-2 Promoter

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

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