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Radiother Oncol. 2001 Dec;61(3):313-20.

Tumor vasculature is targeted by the combination of combretastatin A-4 and hyperthermia.

Author information

1
Department of Oncology, University of Bergen, Haukeland University Hospital, 5021 Bergen, Norway.

Abstract

BACKGROUND AND PURPOSE:

Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT(4)An rat gliomas. We currently investigated how CA-4 and hyperthermia affect the tumor microenvironment and neovasculature to disclose how the two treatment modalities interact to produce tumor response.

METHODS:

By confocal microscopy and immunostaining for von Willebrand factor, we examined the extent of vascular damage subsequent to CA-4 (50 mg/kg) and hyperthermia (waterbath 44 degrees C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO(2)-probes (Licox system) and by immunostaining for pimonidazole. We examined the direct effect of CA-4 on the tumor cell population by flow cytometry (cell cycle distribution) and immunostaining for beta-tubulin (cytoskeletal damage).

RESULTS:

Whereas slight vascular damage was produced by CA-4 in the BT(4)An tumors, local hyperthermia exhibited moderate anti-vascular activity. In tumors exposed to CA-4 3 h before hyperthermia, massive vascular damage ensued. CA-4 reduced the pO(2) from 36.1 to 17.6 mmHg (P=0.01) in the tumor base, and tumor hypoxia increased slightly in the tumor center (pimonidazole staining). Extensive tumor hypoxia developed subsequent to hyperthermia or combination therapy. Despite a profound influence on beta-tubulin organization in vitro, CA-4 had no significant effect on the cell cycle distribution in vivo.

CONCLUSION:

Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.

PMID:
11731002
DOI:
10.1016/s0167-8140(01)00450-9
[Indexed for MEDLINE]

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