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Published on: October 27, 2014
Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR-22R prostate cancer xenografts
1Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore. cmrhth@nccs.com.sg
Abstract:
Prostate cancer is the most common malignancy in men. Although patients with metastatic prostate cancer can benefit from androgen ablation, most of them will die of prostate cancer progression to an androgen-refractory state. In the present study, the effects of docetaxel, bevacizumab, 5-fluorouracil (5-FU), bevacizumab plus docetaxel, and bevacizumab plus 5-FU on the growth of human CWR-22 (androgen-dependent) and CWR-22R (androgen-independent) prostate carcinoma xenografts were investigated. We report that i.p. administration of 10 mg/kg docetaxel at 1-week interval, 5 mg/kg/ bevacizumab once every 2 weeks, or 12.5 mg/kg 5-FU, bevacizumab/docetaxel, or bevacizumab/5-FU weekly to severe combined immunodeficient mice bearing prostate cancer xenografts (12 mice per treatment group) for 21 days resulted in 22.5 +/- 8%, 23 +/- 7%, 31 +/- 8%, 22 +/- 6%, and 81 +/- 5% growth inhibition, respectively. Greatest growth suppression was observed in bevacizumab/5-FU treatment. Bevacizumab/5-FU-induced growth suppression was associated with reduction in microvessel density, inhibition of cell proliferation; up-regulation of phosphatase and tensin homologue, p21(Cip1/Waf1), p16(INK4a), and p27(Kip1); hypophosphorylation of retinoblastoma protein; and inhibition of Akt/mammalian target of rapamycin pathway. Our data indicate that bevacizumab/5-FU effectively inhibits angiogenesis and cell cycle progression and suggest that bevacizumab/5-FU may represent an alternative treatment for patients with prostate cancer.
Insights
The combination of bevacizumab and 5-fluorouracil (5-FU) significantly inhibited prostate cancer xenograft growth. This novel treatment strategy effectively targets angiogenesis and cell cycle progression in advanced prostate cancer.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Prostate cancer is a leading malignancy in men, often progressing to an androgen-refractory state despite androgen ablation therapy.
- Effective treatments for advanced, refractory prostate cancer remain a critical unmet need.
Purpose of the Study:
- To investigate the efficacy of docetaxel, bevacizumab, 5-fluorouracil (5-FU), and their combinations against prostate cancer xenografts.
- To evaluate the anti-angiogenic and anti-proliferative effects of the most effective treatment combination.
Main Methods:
- Human prostate cancer xenografts (androgen-dependent CWR-22 and androgen-independent CWR-22R) were established in severe combined immunodeficient mice.
- Mice received intraperitoneal administration of docetaxel, bevacizumab, 5-FU, bevacizumab/docetaxel, or bevacizumab/5-FU for 21 days.
- Tumor growth inhibition, microvessel density, cell proliferation, and key molecular markers were assessed.
Main Results:
- Bevacizumab plus 5-FU demonstrated the greatest tumor growth inhibition (81 +/- 5%) compared to single agents or bevacizumab/docetaxel.
- Bevacizumab/5-FU treatment led to reduced microvessel density and cell proliferation.
- This combination upregulated tumor suppressor proteins (PTEN, p21, p16, p27) and inhibited the Akt/mTOR pathway.
Conclusions:
- Bevacizumab combined with 5-FU is a highly effective treatment for prostate cancer xenografts.
- This combination therapy inhibits critical pathways involved in tumor growth, including angiogenesis and cell cycle progression.
- Bevacizumab/5-FU presents a promising alternative therapeutic strategy for patients with advanced prostate cancer.
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