Retinoids in the chemoprevention of bladder cancer

Al, Sabichi; Sp, Lerner; Hb, Grossman; Lippman, S. M.

doi:10.1097/00001622-199809000-00019

Cited by 34 publications

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“…Retinoid-induced mRNA expression of several retinoid-responsive genes has been shown previously in human bladder cancer cell lines (18); LRAT activity, meanwhile, has been demonstrated in the livers of vitamin A-deficient rats after retinoid exposure (24). Given the known impact of retinoids on cell growth and differentiation (19), along with the importance of LRAT in maintaining retinoid levels in tissues (25,26), restoration of LRAT expression may provide one molecular mechanism for the effects of retinoids in human bladder cancer, as reviewed previously (3,52,53).…”

Section: Discussionmentioning

confidence: 76%

“…One class of agents that has been investigated for potential chemopreventative and chemotherapeutic effects in TCC is the natural and synthetic analogs of vitamin A, a group of compounds known as retinoids (3). Vitamin A (retinol; ROL) levels have been shown to be significantly lower in the serum of patients with bladder cancer when compared with controls (4).…”

Section: Introductionmentioning

confidence: 99%

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Boorjian¹,

Tickoo²,

Mongan³

et al. 2004

Clinical Cancer Research

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Purpose: Retinoids, which include vitamin A (retinol; ROL) and its derivatives, have been investigated in the treatment of bladder cancer. We have shown that expression of the enzyme lecithin:ROL acyltransferase (LRAT), which converts ROL to retinyl esters, is reduced in several human cancers. Here we evaluated expression of LRAT protein and mRNA in normal and malignant bladder tissue specimens from human patients. We also examined the effect of retinoids on LRAT expression in bladder cancer cell lines.Experimental Design: We evaluated 49 bladder cancer specimens for LRAT protein expression using immunohistochemistry with affinity-purified antibodies to human LRAT. LRAT mRNA expression was assessed using reverse transcription-PCR in bladder specimens from an additional 16 patients. We examined the effect of retinoic acid and ROL on LRAT mRNA expression in five human bladder cancer cell lines.Results: LRAT protein was detected throughout the nonneoplastic bladder epithelium in all of the specimens. In bladder tumors, LRAT protein expression was reduced compared with the nonneoplastic epithelium or was completely absent in 7 of 32 (21.9%) superficial tumors versus 16 of 17 (94.1%) invasive tumors (P < 0.001). All of the nonneoplastic bladder specimens tested (11 of 11) showed LRAT mRNA expression, compared with 5 of 8 (62%) superficial tumors and 0 of 5 (0%) invasive tumors (P ‫؍‬ 0.001). Three of five human bladder cancer cell lines expressed LRAT mRNA independent of retinoid exposure, whereas in two cell lines LRAT mRNA expression was induced by retinoid treatment.Conclusions: We report a significant reduction in LRAT expression in bladder cancer. Moreover, we demonstrate an inverse correlation of LRAT mRNA and protein expression with increasing tumor stage. These data suggest that loss of LRAT expression is associated with invasive bladder cancer.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Boorjian¹,

Tickoo²,

Mongan³

et al. 2004

Clinical Cancer Research

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“…2 Around 70% of cases present as superficial, low grade and noninvasive papillary tumours. 3,4 Despite regular examination of these patients by cystoscopy, frequent transurethral resection and the use of prophylactic BCG immunotherapy, disease reoccurs in 80% of patients of which 15 to 20% progress to muscle-invasive bladder cancer. 5,6 Eighty-seven percent of early-stage patients with muscle-invasive disease survive for 10 years, but most of these patients require radical radiotherapy or cystectomy.…”

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confidence: 99%

Retinoid‐related molecule AGN193198 potently induces G₂M arrest and apoptosis in bladder cancer cells

Reitmair

Shurland

Tsang

et al. 2005

Intl Journal of Cancer

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The novel synthetic retinoid-related molecule 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-propenyl]-benzoic acid (AGN193198) neither binds effectively to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) nor transactivates in RAR-and RXR-mediated reporter assays. Even so, AGN193198 is potent in inducing apoptosis in human prostate and breast carcinoma cells (Keedwell et al., Cancer Res 2004;64:3302-12). Here, we extend these findings to show that AGN193198 potently and rapidly induces apoptosis in bladder carcinoma cell lines. One micromolar of AGN193198 completely abolished the growth of the transitional cell carcinoma lines UM-UC-3 and J82, and the squamous cell carcinoma line SCaBER; the transitional cell papilloma line RT-4 was slightly less sensitive to the growth inhibitory effect of AGN193198. Treated cells accumulated in the G 2 M phase of the cell cycle. This was accompanied by apoptosis, as revealed by staining cells for exposure of phosphatidylserine at their surface (binding of Annexin V) and FACS analysis of propidium iodide labeled cells. As reported for prostate cancer cells, AGN193198 provoked rapid activation of caspases-3 (by 6 hr), -8 (by 16 hr) and -9 (by 6 hr) in bladder cancer cells. These findings suggest that AGN193198 and related compounds, whose mechanism of action does not appear to involve RARs and RXRs, may be useful in the treatment of bladder cancer. ' 2005 Wiley-Liss, Inc.

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“…[43][44][45] Bilharzial patients and bladder cancer patients with squamous cell carcinoma, the most prevalent type in Egypt, showed significantly lower levels of vitamin A than normal male subjects. 44 (4) In vitro and in animal models and in a few human bladder cancer studies, retinoids showed promising anticancer activity. 5,16,36,[46][47][48][49][50] (5) Particularly in our patients, endemic belharziasis besides tobacco smoking and pollution are major Cyp450s inducers that antagonize endogenous retinoids.…”

Section: Discussionmentioning

confidence: 99%

“…After TURT (with or without intravesical therapy), the superficial bladder tumor recurrence rate is 30-70% within 12 months. 4 Various chemotherapeutic combinations could not improve survival despite dose-escalation highlighting the importance of developing novel therapeutic approaches. 5 Vascular endothelial growth factor (VEGF) is the most critical angiogenic factor identified to date.…”

Section: Introductionmentioning

confidence: 99%

The effectiveness of retinoic acid treatment in bladder cancer: Impact on recurrence, survival and TGFα and VEGF as end-point biomarkers.

Hameed

2008

Cancer Biology & Therapy

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Introduction and aims: Being best-studied superficial bladder cancer (SBC) chemopreventives, retinoids' negative studies and toxicity were stumbling. With proper understanding of retinoid metabolism, we aimed at investigating combined ketoconazole (a strong inhibitor of retinoic acid-catabolizing cytochrome P450s) all-trans retinoic acid (Keto-atRA) SBC treatment. VEGF and TGFα levels are end-point pathogenetic biomarkers involved in early SBC.Results: Keto-atRA treatment significantly improved survival time and decreased recurrence rate compared to control disease group, with tolerable and reversible side-effects. Treatment normalized induced levels of VEGF and TGFα with a positive correlation between these cytokines.Material and methods: Seven days after TURT visible tumor(s), combined atRA 1 mg/kg for five days a week + Keto 200 mg twice daily for five days a week for three months were given to 16 patients with SBC stages Ta and T1 with various grades. Three months follow up/20 months used white light cystoscopy and urinary cytology. Recurrence rate and survival time were compared to a retrospective group of 25 patients of comparable age, stage and grade with TURT as sole treatment for SBC. VEGF and TGFα were measured in urine and serum of 12 normal subjects and treated patients. Samples were collected just before TURT, one week after TURT, at the end of one month and at the end of three months of treatment.Conclusions: The combination and schedule used for KetoatRA therapy effectively reduced recurrence rate and increased survival time of SBC patients probably through reduction of VEGF and TGFα as major mitogenic/angiogenic factors; possibly by eliminating malignant cells that produce them.

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Retinoids in the chemoprevention of bladder cancer

Cited by 34 publications

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Retinoid‐related molecule AGN193198 potently induces G₂M arrest and apoptosis in bladder cancer cells

The effectiveness of retinoic acid treatment in bladder cancer: Impact on recurrence, survival and TGFα and VEGF as end-point biomarkers.

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Retinoids in the chemoprevention of bladder cancer

Cited by 34 publications

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Retinoid‐related molecule AGN193198 potently induces G2M arrest and apoptosis in bladder cancer cells

The effectiveness of retinoic acid treatment in bladder cancer: Impact on recurrence, survival and TGFα and VEGF as end-point biomarkers.

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Retinoid‐related molecule AGN193198 potently induces G₂M arrest and apoptosis in bladder cancer cells