Metronomic chemotherapy dosing-schedules with estramustine and temozolomide act synergistically with anti-VEGFR-2 antibody to cause inhibition of human umbilical venous endothelial cell growth.
The effects of 'metronomic' or extended chemotherapy dosing schedules (ECS) are mediated through poorly understood anti-angiogenic mechanisms. ECS combined with biological anti-angiogenic agents have produced promising pre-clinical results.


METHODS
We have expanded the list of agents with an in vitro ECS profile to include the methylating agent temozolomide (Temodal) and the anti-mitotic agent estramustine (Estracyt). These agents were also combined with a specific anti-angiogenic inhibitor IMC-1C11 and a non-specific agent with anti-angiogenic properties, Compound 5h. The in vitro HUVEC ECS model system was optimised and cell proliferation assays undertaken.


RESULTS
As a single agent, estramustine inhibited endothelial cell proliferation with an IC50 of 4.5 microM and was active at 10-33% of the maximum tolerated dose (MTD) from clinical schedules, whilst temozolomide had IC50 of 6.6 microM and was active at 1-6% of MTD. In combination, significant synergy was seen with IMC-1C11 in combination with either drug, whilst modest additive effects were observed with Compound 5h. None of the combinations resulted in significant cytotoxicity or apoptosis.


CONCLUSIONS
The results show that ECS of temozolomide and estramustine can be significantly enhanced when combined with specific anti-angiogenic inhibitors in an in vitro HUVEC system.
Lam
Thomas
T
Postgraduate Medical Institute, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
Hetherington
John W
JW
Greenman
John
J
Little
Samantha
S
Maraveyas
Anthony
A
D000906:Antibodies / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004961:Estramustine / Q000008:administration & dosage*; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage; D000077204:Temozolomide; D013997:Time Factors; D014471:Umbilical Veins / Q000187:drug effects* / Q000254:growth & development; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
D000906:Antibodies; D000911:Antibodies, Monoclonal; C480573:IMC1C11; D004961:Estramustine; D003606:Dacarbazine; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel; D000077204:Temozolomide