Targeting the tumor vasculature with combretastatin A-4 disodium phosphate: effects on radiation therapy.

Abstract

PURPOSE:

The aim of this study was to evaluate the antitumor efficacy of combretastatin A-4 disodium phosphate (combretastatin prodrug) in the rodent KHT sarcoma model either alone or in combination with radiation therapy.

METHODS:

KHT tumors were grown in C3H/HeJ mice. Combretastatin A-4 prodrug was injected intraperitoneally at doses ranging from 10 to 100 mg/kg. Tumors were irradiated in unanesthetized mice using a 137Cs source. Tumor response to combretastatin A-4 prodrug was assessed by histological evaluations as well as an in vivo to in vitro cell survival assay.

RESULTS:

Histological evaluation showed morphological damage of tumor cells within a few hours after drug treatment, followed by extensive central necrosis. Administering increasing doses of combretastatin A-4 prodrug to tumor-bearing mice resulted in a dose-dependent increase in cell killing irrespective of whether the tumors were irradiated or not. When combined with radiation, a 100 mg/kg dose of combretastatin A-4 prodrug reduced tumor cell survival 10-500-fold lower than that seen with radiation alone. Further, the shape of the cell survival curve observed following the combination therapy suggested that including combretastatin in the treatment had a major effect on the radiation-resistant hypoxic cell subpopulation associated with this tumor.

CONCLUSION:

The present results demonstrated that in the KHT sarcoma, combretastatin A-4 prodrug caused rapid vascular shutdown, a concentration-dependent direct cell killing, and effective enhancement of the antitumor effects of radiation therapy.

• Authors: L Li, A Rojiani, D W Siemann
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 42 Issue 4 Pg. 899-903 (Nov 01 1998) ISSN: 0360-3016 [Print] United States
• PMID: 9845118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Stilbenes
• fosbretabulin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Blood Vessels (drug effects)
• Combined Modality Therapy
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Mice
• Mice, Inbred C3H
• Necrosis
• Sarcoma, Experimental (blood supply, pathology, radiotherapy)
• Stilbenes (pharmacology)