In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment

Purpose: Interference with the tumor blood vessels through anti-angiogenesi s or vascular targeting can indirectly suppress tumor growth. Vascular targ eting of solid tumors, using tubulin-compromising agents, seems a promising and selective novel treatment. We aimed to evaluate the potential (hypothe sis-based) benefit from combinations of vascular targeting using combretast atin A-4 phosphate (combreAp) with either ionizing radiation or anti-angiog enesis. Methods and Materials: Rhabdomyosarcoma tumor pieces were inplanted subcuta neously (s.c.) in the lower Rank region of syngeneic adult WAG/Rij rats, Tu mors were groan until different sizes and stratified for the various treatm ent groups: small (1-3 cm(3)), medium (3.1-7 cm(3)), and large (7.1-14 cm(3 )), CombreAp was injected i.p.; injections of TNP-470 were s.c. in the neck area. Localized single-dose (8 Gy) irradiations of tumors were done under Nembutal anesthesia, always 1 day before a single combreAp (25 mg/kg) injec tion. The TNP-470 treatment (3 times 30 mg/kg in 1 week) started I day afte r a double (8 days interval between both) combreAp administration. Tumor re sponses were evaluated by the growth delay assay, and statistical significa nce of tumor growth change was computed. Results: Large tumors responded better to combreAp treatment given alone th an did the smaller ones, confirming our previous data with this tumor model . Combining irradiation with combreAp also resulted in a tumor size-depende nt growth delay. With small and medium tumor volumes, a similar response wa s measured after the combination treatment when compared with irradiation o nly. Large tumors, however, showed a strong (at Least additive) increase of the growth delay with the combined therapy; the difference in tumor growth between the two treatment groups was very significant (p < 0.0001), When TNP-470 was combined with combreAp, no significant lengthening of the growth delay, irrespective of the tumor size, was present with the applied schedule. Conclusion: The current data show a significant advantage in the combinatio n of combreAp with irradiation in rhabdomyosarcomas having a large size (7- 14 cm(3)) at treatment. Such a benefit in tumor response was not observed w ith the smaller tumors, seemingly because irradiation as such was very effe ctive. No significant gain in growth delay for any tumor size was observed when TNP-470, showing efficacy on its own specifically with tumors measurin g <7 cm(3), was added to the combreAp treatment. This presumably reflects o nly little angiogenesis during the first week of rhabdomyosarcoma regrowth after the combreAp treatment. (C) 2001 Elsevier Science Inc.