Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors

Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1233-40. doi: 10.1016/j.ijrobp.2004.08.002.

Abstract

Purpose: To evaluate the antitumor efficacy of a vascular targeting strategy that combines an agent that disrupts established tumor blood vessels (ZD6126) with one that interferes with new vessel formation (ZD6474) in models of human renal cell carcinoma (Caki-1) and Kaposi's sarcoma (KSY-1).

Methods and materials: Caki-1 and KSY-1 xenograft-bearing nude mice were treated with ZD6126 and ZD6474 either as single agents or in combination when the tumors reached a size of approximately 200 mm(3). ZD6126 therapy consisted of three doses of 100 mg/kg administered 1, 3, and 5 days after the tumor reached the starting size. ZD6474 was administered daily (25 mg/kg) on Days 1-5. In the combination studies, ZD6474 treatment began immediately after the first dose of ZD6126. The tumor response to treatment was evaluated using a regrowth delay endpoint.

Results: Significant tumor growth delays were observed in both tumor models with either agent with the treatment regimen used. In the Caki-1 and KSY-1 models, respectively, ZD6126 treatment resulted in a tumor growth delay of 23 and 26 days and ZD6474 produced a tumor growth delay of 24.5 and 14.5 days. When ZD6126 and ZD6474 were combined, the tumor growth delays increased to 55 (Caki-1) and 86 (KSY-1) days. In the KSY-1 model, the combination therapy also resulted in 3 of 8 long-term tumor-free survivors.

Conclusion: These results indicate that statistically significant antitumor efficacy can be achieved using a treatment strategy that combines a therapy that targets the established tumor blood vessels with one that interferes with the process of angiogenesis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Carcinoma, Renal Cell / blood supply
  • Drug Screening Assays, Antitumor / methods
  • Drug Therapy, Combination
  • Female
  • Humans
  • Kidney Neoplasms / blood supply
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / prevention & control*
  • Organophosphorus Compounds / administration & dosage*
  • Piperidines / administration & dosage*
  • Quinazolines / administration & dosage*
  • Sarcoma, Kaposi / blood supply

Substances

  • Angiogenesis Inhibitors
  • N-acetylcochinol-O-phosphate
  • Organophosphorus Compounds
  • Piperidines
  • Quinazolines
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine