Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects.

Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE

Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]

Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Squamous Cell/*drug therapy ; Head and Neck Neoplasms/*drug therapy ; Neovascularization, Pathologic/*drug therapy; Animals ; Carcinoma, Squamous Cell/blood supply ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Docetaxel ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Synergism ; Endothelial Cells/drug effects ; Endothelial Cells/physiology ; Gossypol/administration & dosage ; Gossypol/analogs & derivatives ; Gossypol/pharmacology ; Head and Neck Neoplasms/blood supply ; Head and Neck Neoplasms/pathology ; Humans ; Inhibitory Concentration 50 ; Kaplan-Meier Estimate ; Male ; Mice ; Mice, SCID ; Neovascularization, Pathologic/pathology ; Neovascularization, Physiologic/drug effects ; Taxoids/administration & dosage ; Treatment Outcome ; Xenograft Model Antitumor Assays

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.
(©2011 AACR.)

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R01 DE016586-05 United States DE NIDCR NIH HHS; P50 CA097248 United States CA NCI NIH HHS; U19-CA113317 United States CA NCI NIH HHS; R01-DE15948 United States DE NIDCR NIH HHS; P50-CA97248 United States CA NCI NIH HHS; R01 DE014601 United States DE NIDCR NIH HHS; R01 DE021139 United States DE NIDCR NIH HHS; R01 DE014601-05 United States DE NIDCR NIH HHS; R01-DE14601 United States DE NIDCR NIH HHS; R01 DE016586 United States DE NIDCR NIH HHS; R01-DE16586 United States DE NIDCR NIH HHS; R01 DE015948 United States DE NIDCR NIH HHS; R21-DE19279 United States DE NIDCR NIH HHS; R01 DE015948-05 United States DE NIDCR NIH HHS; U19 CA113317 United States CA NCI NIH HHS; R21 DE019279 United States DE NIDCR NIH HHS

0 (Taxoids)
15H5577CQD (Docetaxel)
KAV15B369O (Gossypol)
S7RL72610R (gossypol acetic acid)

Date Created: 20111214 Date Completed: 20120330 Latest Revision: 20211021

20221213

PMC3748951

10.1158/0008-5472.CAN-10-2873

22158856