Anti-tumour and anti-vascular effects of cediranib (AZD2171) alone and in combination with other anti-tumour therapies.
OBJECTIVE
Cediranib (AZD2171) is a highly potent inhibitor of all three vascular endothelial growth factor receptors. The aim of this preclinical study was to examine the effect of combining cediranib with mechanistically distinct anti-tumour therapies.


METHODS
Cediranib (1.5 or 3 mg/kg/day) was evaluated alone and in combination with either gefitinib, imatinib, ZD6126, saracatinib, selumetinib, bevacizumab, 5-fluorouracil (5-FU), docetaxel, oxaliplatin, gemcitabine, pemetrexed, irinotecan or cisplatin in human tumour xenograft models. Anti-tumour activity was measured by assessing the change in tumour volume following treatment compared with vehicle-treated time-matched controls.


RESULTS
In all cases, the combination regimens, at tolerated doses and schedules, inhibited tumour growth to a greater extent than the corresponding monotherapy treatments. Compared with cediranib alone, statistically significant enhancements in anti-tumour activity were observed with all combination regimens. Notably, after 14 days of treatment, the combination of cediranib with ZD6126 induced substantial tumour regression (60 % compared with pre-treatment volume), whilst treatment with each agent alone led only to partial growth inhibition. A combination of cediranib with gefitinib also induced tumour regressions, and cediranib combined with either gemcitabine or irinotecan was found to inhibit tumour growth profoundly (by 99 and 98 %, respectively).


CONCLUSIONS
Combining cediranib with selected cytotoxic or targeted agents proved efficacious in a range of human tumour xenograft models.
Translational Sciences, AstraZeneca Oncology, Alderley Park, Macclesfield SK10 4TF, UK.
Jane
J
Kendrew
Rajesh
R
Odedra
Armelle
A
Logié
Paula J
PJ
Taylor
Sharon
S
Pearsall
Donald J
DJ
Ogilvie
Stephen R
SR
Wedge
Juliane M
JM
Jürgensmeier
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
D000970:Antineoplastic Agents; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles