Alternative scheduling of pulsatile, high dose sunitinib efficiently suppresses tumor growth.
Increased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels. The currently approved schedule (50 mg daily, four weeks on, two weeks off) precludes further dose-intensification. Recent data suggest that sunitinib, although initially developed as an antiangiogenic agent, has direct antitumor activity.



In this study, we tested whether a chemotherapy-like schedule of pulsatile high dose sunitinib would result in improved antitumor activity.



In vitro, a single exposure to 20 μM sunitinib for 6-9 h resulted in complete inhibition of tumor cell growth and cell death conveyed through activation of caspases and autophagy upregulation. Notably, repeated exposure of tumor cells to pulses of high concentrations of sunitinib did not induce resistance. In vivo, once-weekly treatment with high dose sunitinib of tumors growing on the chorioallantoic membrane (CAM) of the chicken embryo significantly impaired tumor growth by 57 % compared to vehicle, outperforming the daily, standard scheduling.



These results prompted the initiation of a phase I clinical trial, where intermittent, high dose sunitinib is being investigated in patients with advanced solid tumors (registration number and date: NCT02058901, 30 September 2013, respectively). The trial is actively recruiting patients and promising preliminary indications of antitumor activity have been observed.
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Maria
M
Rovithi
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Richard R
RR
de Haas
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Richard J
RJ
Honeywell
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Dennis
D
Poel
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Godefridus J
GJ
Peters
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Arjan W
AW
Griffioen
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. h.verheul@vumc.nl.
Henk M W
HM
Verheul
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D020551:Pulse Therapy, Drug; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D020169:Caspases; D000077210:Sunitinib
Alternative scheduling; Apoptosis; Autophagy; CAM model; Cancer; High dose; Pulsatile; Sunitinib; Tumor growth