title: Tumor vasculature is targeted by the combination of combretastatin A-4 and hyperthermia.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.
authors.affiliation: Department of Oncology, University of Bergen, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: H P
authors.initials: HP
authors.lastname: Eikesdal
authors.forename: R
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: J A
authors.initials: JA
authors.lastname: Raleigh
authors.forename: O
authors.initials: O
authors.lastname: Mella
authors.forename: O
authors.initials: O
authors.lastname: Dahl
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D005910:Glioma / Q000098:blood supply* / Q000628:therapy*; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C058728:fosbretabulin