A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses

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J Clin Oncol. 2005 Feb 10;23(5):939-52. Epub 2004 Nov 22.

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Pietras K, Hanahan D.
Department
of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer
Centers, University of California San Francisco, 513 Parnassas Avenue,
San Francisco, CA 94143, USA.
 
PURPOSE: A
transgenic mouse model has revealed parameters of the angiogenic switch
during multistep tumorigenesis of pancreatic islets, and demonstrated
efficacy of antiangiogenic therapies. Pericytes have been revealed as
functionally important for tumor neovasculature, using kinase
inhibitors targeting their platelet-derived growth factor receptors
(PDGFRs). Additionally, vascular endothelial growth factor receptor
(VEGFR) inhibitors and metronomic chemotherapy show modest benefit
against early- but not late-stage disease.
 
MATERIALS AND METHODS:
Seeking to improve efficacy against otherwise intractable end-stage
pancreatic islet tumors, two receptor tyrosine kinase inhibitors,
imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte
support of tumor endothelial cells in concert with maximum-tolerated
dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition.
 
RESULTS:
Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte
coverage of tumor vessels and enhanced efficacy in combination with
metronomic chemotherapy or VEGFR inhibition. A regimen involving all
three was even better. MTD using cyclophosphamide caused transitory
regression, but then rapid regrowth, in contrast to metronomic
cyclophosphamide plus imatinib, which produced stable disease. The MTD
regimen elicited apoptosis of tumor cells but not endothelial cells,
whereas the other regimens increased endothelial cell apoptosis
concordant with efficacy. A "chemo-switch" protocol, involving
sequential MTD and then metronomic chemotherapy, overlaid with
multitargeted inhibition of PDGFR and VEGFR, gave complete responses
and unprecedented survival advantage in this model.

CONCLUSION: This
study demonstrates a potentially tractable clinical strategy in a
stringent preclinical model, wherein standard-of-care chemotherapy is
followed by a novel maintenance regimen: PDFGR is targeted to disrupt
pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors
target consequently sensitized endothelial cells, collectively
destabilizing pre-existing tumor vasculature and inhibiting ongoing
angiogenesis.