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Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent®) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer

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Abstract

Purpose

Physiological and molecular findings indicate over-expression of HER proteins and dysregulation of neo-angiogenesis during progression of advanced prostate cancer. The aim of this study was to test a novel rational therapeutic approach by combining docetaxel with an EGFR-targeting agent (cetuximab) and with an anti-angiogenic agent (sunitinib, SUTENT®).

Methods

Mice bearing well-established PC3 prostate tumors (mean tumor volume/treatment group ∼250 mm3) were treated every week with vehicle alone (controls), sunitinib (40 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml p.o.), cetuximab (0.2 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml i.p.) and docetaxel (10 mg/kg, 1 day/week for 3 weeks, 0.2 ml i.p.).

Results

Each drug, administered as a single-agent, demonstrated comparable and moderate effects on tumor growth with approximately 50 % inhibition at the end of the 3-week dosing schedule. Computed combination ratio (CR) values for tumor growth determined on days 61, 68 and 75 after cell implantation indicated supra-additive effects for the sunitinib-docetaxel (1.53, 1.15 and 1.47, respectively) and sunitinib–cetuximab combinations (1.2, 1.32 and 1.14, respectively), and suggested additive effects only for the sunitinib–cetuximab–docetaxel combination (CR = 1). The effects on tumor growth were accompanied by a parallel diminution in tumor cell proliferation (Ki 67) and tumor vascularization (von Willebrandt factor). There were significantly higher pro-apoptotic effects (caspase-3 cleavage) observed for the sunitinib–docetaxel and sunitinib–docetaxel–cetuximab as compared to the other conditions.

Conclusion

The supra-additive anti-tumor effect observed with the sunitinib–docetaxel combination might support innovative strategies in the management of advanced prostate cancer.

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Acknowledgment

PFIZER France is acknowledged for the financial support of this work.

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Authors and Affiliations

  1. Nice General Hospital, Nice, France

    O. Guérin & P. Hofman

  2. Oncopharmacology Unit, Centre Antoine Lacassagne, 33, Avenue de Valombrose, 06189, Nice Cedex 2, France

    P. Formento, J. L. Fischel, M. C. Etienne-Grimaldi, J. M. Ferrero & G. Milano

  3. Laboratorio Oncologia Translazionale, ASO S. Croce e Carle, Cuneo, Italy

    C. Lo Nigro & M. Merlano

Authors
  1. O. Guérin
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  2. P. Formento
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  3. C. Lo Nigro
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  4. P. Hofman
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  5. J. L. Fischel
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  6. M. C. Etienne-Grimaldi
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  7. M. Merlano
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  8. J. M. Ferrero
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  9. G. Milano
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Corresponding author

Correspondence to G. Milano.

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Guérin, O., Formento, P., Lo Nigro, C. et al. Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent®) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer. J Cancer Res Clin Oncol 134, 51–57 (2008). https://doi.org/10.1007/s00432-007-0247-4

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  • DOI: https://doi.org/10.1007/s00432-007-0247-4

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