In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment.
OBJECTIVE
Interference with the tumor blood vessels through anti-angiogenesis or vascular targeting can indirectly suppress tumor growth. Vascular targeting of solid tumors, using tubulin-compromising agents, seems a promising and selective novel treatment. We aimed to evaluate the potential (hypothesis-based) benefit from combinations of vascular targeting using combretastatin A-4 phosphate (combreAp) with either ionizing radiation or anti-angiogenesis.


METHODS
Rhabdomyosarcoma tumor pieces were inplanted subcutaneously (s.c.) in the lower flank region of syngeneic adult WAG/Rij rats. Tumors were grown until different sizes and stratified for the various treatment groups: small (1-3 cm3), medium (3.1-7 cm3), and large (7.1-14 cm3). 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) injection. The TNP-470 treatment (3 times 30 mg/kg in 1 week) started 1 day after a double (8 days interval between both) combreAp administration. Tumor responses were evaluated by the growth delay assay, and statistical significance of tumor growth change was computed.


RESULTS
Large tumors responded better to combreAp treatment given alone than did the smaller ones, confirming our previous data with this tumor model. Combining irradiation with combreAp also resulted in a tumor size-dependent growth delay. With small and medium tumor volumes, a similar response was measured after the combination treatment when compared with irradiation only. 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). m 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.


CONCLUSIONS
The current data show a significant advantage in the combination of combreAp with irradiation in rhabdomyosarcomas having a large size (7-14 cm3) at treatment. Such a benefit in tumor response was not observed with the smaller tumors, seemingly because irradiation as such was very effective. No significant gain in growth delay for any tumor size was observed when TNP-470, showing efficacy on its own specifically with tumors measuring <7 cm3, was added to the combreAp treatment. This presumably reflects only little angiogenesis during the first week of rhabdomyosarcoma regrowth after the combreAp treatment.
Landuyt
W
W
Laboratory of Experimental Radiobiology, University Hospital Gasthuisberg, Leuven, Belgium. willy.landuyt@rega.kulenven.ac.be
Ahmed
B
B
Nuyts
S
S
Theys
J
J
Op de Beeck
M
M
Rijnders
A
A
Anné
J
J
van Oosterom
A
A
van den Bogaert
W
W
Lambin
P
P
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003510:Cyclohexanes; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011879:Radiotherapy Dosage; D051381:Rats; D012208:Rhabdomyosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013267:Stilbenes / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D013267:Stilbenes; C058728:fosbretabulin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol