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

Abstract

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.

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

“…ILC2 that produce IL-13 (67); and (c) a meta-analysis showed that vitamin A plays a protective role in BCa (68), and ATRA treatment was found to significantly improve survival and recurrence rates in NMIBC patients (69). Furthermore, a combination of depletion or attenuation of MDSCs and concomitant stimulation of effector T cells may be of interest.…”

CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer

“…In breast cancer, CRBP1 down-regulation promoted the progression of tumors through the inhibition of RA receptor activity (24). In terms of BC, RA treatment effectively reduced the recurrence rate and increased the survival time of superficial BC patients (26,27). However, there have been no gain-of-function studies on the CRBP1 gene.…”

Chemoprevention and Novel Treatments of Non-Muscle Invasive Bladder Cancer

“…Results for these trials were mixed, with some showing significant preventative effects (Alfthan et al, 1983;Studer et al, 1995;Yoshida et al, 1986) and others showing less promising results (Decensi et al, 2000;Prout & Barton, 1992). Mild to severe toxicities were also noted in many of these studies and may potentially limit vitamin A's use as a chemopreventive agent (Hameed & el-Metwally, 2008). More recently, to enable lower doses of retinoic acids and decrease unwanted side effects, combinations of retinoic acid and inhibitors of the CYP26A enzyme (involved in degradation of vitamin A) have been explored with some success (Hameed & el-Metwally, 2008).…”

“…Mild to severe toxicities were also noted in many of these studies and may potentially limit vitamin A's use as a chemopreventive agent (Hameed & el-Metwally, 2008). More recently, to enable lower doses of retinoic acids and decrease unwanted side effects, combinations of retinoic acid and inhibitors of the CYP26A enzyme (involved in degradation of vitamin A) have been explored with some success (Hameed & el-Metwally, 2008). Although a recent cohort study showed no significant association of several vitamins including retinoids with urothelial carcinoma risk (Hotaling et al, 2011), other past studies provide some compelling evidence for vitamin A's efficacy.…”

“…Additionally, vitamin A's anti-tumor activity may involve, among others, interactions with growth factors and cytokines, neoplastic stem cell pathways such as WNT, cAMP pathways, mitogen activated protein kinases (MAPKs), PI3K/AKT, cyclin-dependent kinases (CDKs), protein kinase C, and epigenetic modulation of gene expression (Garattini et al, 2007). Other studies indicate that some synthetic retinoids may even reduce VEGF expression, which is an important angiogenic factor in bladder cancer growth (Hameed & el-Metwally, 2008). Several studies have examined vitamin A and its derivatives for chemoprevention of bladder cancer.…”