Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer.
Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials.
Holtz
David O
DO
Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania, Philadelphia, USA. HoltzD@MLHS.ORG
Krafty
Robert T
RT
Mohamed-Hadley
Alisha
A
Zhang
Lin
L
Alagkiozidis
Ioannis
I
Leiby
Benjamin
B
Guo
Wensheng
W
Gimotty
Phyllis A
PA
Coukos
George
G
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D017239:Paclitaxel