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Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2012 Mar; Vol. 11 (3), pp. 680-9. Date of Electronic Publication: 2011 Dec 21. - Publication Year :
- 2012
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Abstract
- Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow-derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor-bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.
- Subjects :
- Administration, Oral
Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic pharmacology
Blood Vessels drug effects
Blood Vessels metabolism
Blood Vessels pathology
Cell Line, Tumor
Deoxycytidine administration & dosage
Deoxycytidine pharmacology
Dose-Response Relationship, Drug
Endothelial Cells drug effects
Endothelial Cells metabolism
Female
Humans
Mice
Mice, Inbred BALB C
Mice, SCID
Neoplasms blood supply
Neoplasms pathology
Neovascularization, Pathologic prevention & control
Prodrugs administration & dosage
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Gemcitabine
Deoxycytidine analogs & derivatives
Neoplasms drug therapy
Prodrugs pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 11
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 22188817
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-11-0659