Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts.

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Oncogene. 2008 Jun 12;27(26):3729-38. Epub 2008 Jan 28.
 
Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts.
 
Shahrzad S, Shirasawa S, Sasazuki T, Rak JW, Coomber BL
.Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
 
Antiangiogenic
therapies are promising approaches to cancer control, but the details
of their effects on subsequent tumor progression are not fully
understood. Such therapies have the potential to eventually generate
extensive amounts of tumor ischemia, and we previously demonstrated
that ischemic conditions induce K-ras mutations in cells with deficient
mismatch repair (MMR) mechanisms. This suggested that similar effects
on oncogene mutagenesis may accompany antiangiogenic therapy.
 
To test
this, MMR-deficient colorectal cancer cells (Dks-8) were xenografted
into immune-deficient mice and treated with the antiangiogenic regimen
of low-dose/metronomic cyclophosphamide for 2 weeks followed by a
2-week recovery period without therapy. This treatment resulted in
transient tumor growth inhibition, increased hypoxia, and decreased
microvessel density, and cancer cells from treated tumors acquired
activating mutations of the K-ras oncogene (K-ras(G13D)).
 
In vitro
exposure of Dks-8 cells to the active metabolite of cyclophosphamide
(4-hydroxycyclophosphamide) had no effect on the K-ras status,
indicating that there was no direct action of this alkylating agent on
K-ras mutagenesis. In addition, cells sorted from hypoxic regions of
Dks-8 tumors were enriched in K-ras(G13D) mutants. Collectively, our
studies suggest that increases in tumor hypoxia induced by
antiangiogenic treatment may lead to K-ras mutation and consequently
tumor progression, especially in susceptible individuals.