Continuous low-dose (metronomic) chemotherapy on rat prostate tumors evaluated using MRI in vivo and comparison with histology

Neoplasia. 2005 Jul;7(7):678-87. doi: 10.1593/neo.04757.

Abstract

Continuous low-dose (metronomic) therapy, based on cyclophosphamide (CTX) combined with thalidomide (Tha), was evaluated on Dunning prostate R3327-AT1 rat tumors. Significantly delayed tumor growth (P < .001) was observed with oral CTX alone at a low dose (metronomic cyclophosphamide or M-CTX; 30 mg/kg per day) or combined with Tha. To investigate dynamic changes in tumor physiology during early stages of treatment, magnetic resonance imaging (MRI) was applied before and during the M-CTX or M-CTX + Tha therapy. Dynamic contrast-enhanced MRI revealed significant changes in the tumor center by day 3 (P < .01); by day 7, only a thin peripheral tumor region showed high signal enhancement. There was a significant correlation between poorly enhancing fraction on day 7 and ultimate tumor growth delay (P < .02). The apparent transverse relaxation rate (R2*) showed similar baseline tumor heterogeneity, but no obvious changes with growth or therapy. Histology confirmed substantial necrosis in the tumor center, leaving a thin live peripheral rim. Immunohistochemistry showed a significant increase in vascular endothelial growth factor, and apoptotic tumor and vascular endothelial cells. These results show the efficacy of the metronomic CTX +/- Tha for delaying tumor growth and indicate that MRI provides insights into the mode of action and early indication of efficacy.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Area Under Curve
  • Cyclophosphamide / administration & dosage
  • Hypoxia
  • Immunohistochemistry / methods
  • Magnetic Resonance Imaging / methods*
  • Male
  • Necrosis
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Rats
  • Thalidomide / administration & dosage
  • Time Factors
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Thalidomide
  • Cyclophosphamide