Dosing of rapamycin is critical to achieve an optimal antiangiogenic effect against cancer

Abstract

Summary 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.

Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APCMin/+ mice

“…A low, continuous, dosing regime could provide an optimized treatment effect, while avoiding the most severe side effects of high peak levels. This idea is supported by our earlier studies showing that the antitumor effect of rapamycin decreases with high bolus dosing (Guba et al, 2005). Dosing could be a critical factor if mTOR inhibitors are eventually used in FAP patients, who are often young and might need to take the medication life long.…”

Survival Benefit With Proapoptotic Molecular and Pathologic Responses From Dual Targeting of Mammalian Target of Rapamycin and Epidermal Growth Factor Receptor in a Preclinical Model of Pancreatic Neuroendocrine Carcinogenesis

“…1,11 Interestingly, although we envisioned that rapamycin might impair inflammation and/or angiogenesis, 6,8 the primary effect was on the cancer cells, where it elicited increased rates of apoptosis and impaired cell division, with no evident effects on the tumor vasculature (Data Supplement Fig 5).…”

“…[3][4][5] Rapamycin is a potent and specific inhibitor of mTOR and has been shown to inhibit tumor growth, angiogenesis, and metastasis, as well as induce apoptosis in cancer cell lines and in mouse models of cancer. [6][7][8] Two rapamycin analogs ("rapalogs"), everolimus and temsirolimus, have been approved for treatment of advanced renal cell carcinoma after failure of chemotherapy. 9 In PNET, everolimus has been shown to have efficacy against metastatic PNET after failure of cytotoxic chemotherapy in a phase II trial and is being evaluated in a phase III trial as a first-line option for treating PNET.…”

Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging

“…Rapamycin and derivatives possess a broad antitumor activity, which comprises antitumor cell antiangiogenic and antivascular activities (42,43), but the dosing regimen is critical to achieve an optimal antiangiogenic effect (44). RAD001 also possesses broad antitumor activity, including antiangiogenic activity, manifested by a reduction in tumor VEGF production and vascular density (45,46).…”