Dosing of rapamycin is critical to achieve an optimal antiangiogenic effect against cancer.
Rapamycin has antiangiogenic activity against tumors. This has been discussed while addressing the problem of cancer in organ transplantation. Here we investigated effective dosing schedules against tumors and angiogenesis. Growth of established CT-26 colon adenocarcinoma tumors was measured in Balb/c mice treated with total equivalent rapamycin doses (1.5 mg/kg/day) given once a day, once every 3 days, or by continuous infusion. Tumors were most inhibited with continuous rapamycin infusion, and less by bolus dosing. Interestingly, however, continuous dosing produced the lowest rapamycin blood levels (15 ng/ml). As rapamycin-sensitive p70S6-kinase intracellular signaling is critical for angiogenesis, p70S6-kinase activation was measured in endothelial cells by Western blotting. Maximal p70S6-kinase inhibition occurred from 1-5 ng/ml rapamycin. These same rapamycin concentrations optimally blocked vessel-sprouting from cultured aortic rings. Therefore, low-level rapamycin dosing most effectively controls tumors in mice. Importantly, antiangiogenic rapamycin levels are compatible with immunosuppressive doses, supporting its potential use in transplant patients with cancer.
Guba
Markus
M
Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
Koehl
Gudrun E
GE
Neppl
Evelyn
E
Doenecke
Axel
A
Steinbauer
Markus
M
Schlitt
Hans J
HJ
Jauch
Karl-Walter
KW
Geissler
Edward K
EK
D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D020123:Sirolimus