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

Cancer Biol Ther. 2008 Jan;7(1):92-100. doi: 10.4161/cbt.7.1.5134. Epub 2007 Oct 8.


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 TGFalpha 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 TGFalpha 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 TGFalpha 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 Keto-atRA therapy effectively reduced recurrence rate and increased survival time of SBC patients probably through reduction of VEGF and TGFalpha as major mitogenic/angiogenic factors; possibly by eliminating malignant cells that produce them.

MeSH terms

  • Aged
  • Biomarkers
  • Cytochrome P-450 Enzyme System / physiology
  • Drug Therapy, Combination
  • Humans
  • Ketoconazole / administration & dosage*
  • Middle Aged
  • Neoplasm Recurrence, Local / prevention & control*
  • Transforming Growth Factor alpha / analysis*
  • Transforming Growth Factor alpha / blood
  • Transforming Growth Factor alpha / urine
  • Tretinoin / administration & dosage*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / mortality
  • Vascular Endothelial Growth Factor A / analysis*
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor A / urine


  • Biomarkers
  • Transforming Growth Factor alpha
  • Vascular Endothelial Growth Factor A
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • Ketoconazole