Abstract
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 language | English |
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Pages (from-to) | 313-320 |
Number of pages | 8 |
Journal | Radiotherapy and Oncology |
Volume | 61 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2001 |
Externally published | Yes |
Keywords
- Combretastatin A-4 disodium phosphate
- Confocal microscopy
- Hyperthermia
- Pimonidazole
- Tumor oxygenation