Intratumor injection of the Hsp90 inhibitor 17AAG decreases tumor growth and induces apoptosis in a prostate cancer xenograft model

J Urol. 2007 Oct;178(4 Pt 1):1528-32. doi: 10.1016/j.juro.2007.05.120. Epub 2007 Aug 16.

Abstract

Purpose: A role for heat shock protein 90 inhibitors in prostate cancer has been explored only in the context of systemic treatment of refractory metastatic disease. We hypothesized that intratumor administration of heat shock protein 90 inhibitors may have benefit for treating localized prostate cancer.

Materials and methods: Twice weekly intratumor injections of 50 mg/kg 17AAG (treatment group of 8 mice) or dimethyl sulfoxide (control group of 8) were performed in subcutaneously grown DU-145 prostate cancer xenografts for a total of 8 doses. Tumor size was monitored. An additional tumor nonintervention control group of 3 mice was maintained.

Results: Seven of the 8 mice (88%) in the 17AAG group lived to study completion, of which 6 (86%) showed decreased tumor size and growth rate compared to those of vehicle treated controls (p <0.05). Gross necropsy, and tumor histological and molecular evaluations were performed after sacrifice. No overt signs of systemic toxicity, evidence of distant metastases or peritumor tissue effects were noted. Histologically 17AAG treated tumors were characterized by marked necrosis, inflammation and complete destruction of cellular architecture. Intratumor 17AAG treatment also resulted in pharmacodynamic changes consistent with apoptosis.

Conclusions: The current data demonstrate that intratumor administration of 17AAG promotes tumor growth inhibition, pertinent client protein responses and localized induction of apoptosis together with minimal clinical toxicity. These data support further preclinical evaluation of this treatment modality alone and in combination with other established noninvasive therapy for localized prostate cancer.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzoquinones / pharmacology*
  • Cell Division / drug effects*
  • Cell Line, Tumor
  • Disease Models, Animal*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Injections, Intralesional
  • Lactams, Macrocyclic / pharmacology*
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Prostate / drug effects
  • Prostate / pathology
  • Prostatic Neoplasms / pathology*
  • Transplantation, Heterologous

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • tanespimycin