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

Hans Petter Eikesdal*, Rolf Bjerkvig, James A. Raleigh, Olav Mella, Olav Dahl

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)


Background and purpose: Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT4An 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°C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO2-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 β-tubulin (cytoskeletal damage). Results: Whereas slight vascular damage was produced by CA-4 in the BT4An 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 pO2 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 β-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.

Original languageEnglish
Pages (from-to)313-320
Number of pages8
JournalRadiotherapy and Oncology
Issue number3
Publication statusPublished - 2001
Externally publishedYes


  • Combretastatin A-4 disodium phosphate
  • Confocal microscopy
  • Hyperthermia
  • Pimonidazole
  • Tumor oxygenation


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