An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma.
OBJECTIVE
TNP-470, a synthetic analogue of fumagillin which is a natural product of Aspergillus fumigatus, has been noted as an angiogenesis inhibitor. Combined effects of TNP-470 with fractionated radiotherapy (RT) were investigated using a mouse tumor.


METHODS
Tumors were early generations of mammary carcinoma in C3H/He mice. Treatments were initiated when tumors reached an average diameter of 4-5 mm. Tumor response was evaluated by tumor growth (TG) time assay and 50% tumor control dose (TCD50) assay. Tumors were irradiated locally under hypoxic conditions or in air. Five fractionated radiation doses were given in the TG time assay, whereas a single dose or 10 fractionated doses were given in the TCD50 assay. TNP-470 (100 mg/kg) was administered subcutaneously twice a week during and/or after RT.


RESULTS
In the TG time assay, significant delay of tumor growth was observed by TNP-470 alone (100 mg/kg x 2) compared with control tumors (p < 0.001), indicating that TNP-470 alone has an antitumor effect in vivo. When TNP-470 was administered during fractionated RT, no additional delay of tumor growth was observed. However, additive effects of TNP-470 was noted when it was given after the end of fractionated RT. In the TCD50 assay, no significant difference in TCD50s was observed between RT alone and RT combined with TNP-470 in single dose experiments. Hypoxic fraction of tumors calculated from the TCD50s was not affected significantly by administrating TNP-470 24 h before RT. On the other hand, in 10-fraction experiments, the TCD50 (RT with TNP-470, in air) was significantly higher than the TCD50 (RT alone, in air) (p < 0.005), indicating that TNP-470 given during fractionated RT decreased radiocurability. This negative effect of TNP-470 was not observed when TNP-470 was combined with fractionated RT given under hypoxic conditions.


CONCLUSIONS
The tumor control probability decreased by administrating TNP-470 during fractionated RT in air. This unexpected result may be attributable to partial inhibition of reoxygenation by TNP-470, because no significant difference was noted between the TCD50 (RT with TNP-470) and the TCD50 (RT alone) under hypoxic conditions.
Murata
R
R
Department of Radiology, Faculty of Medicine, Kyoto University, Sakyo-ku, Japan.
Nishimura
Y
Y
Hiraoka
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D003131:Combined Modality Therapy / Q000379:methods; D003510:Cyclohexanes; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol