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

S. Shahrzad, S. Shirasawa, Takehiko Sasazuki, J. W. Rak, B. L. Coomber

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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-rasG13D). 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-rasG13D 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.

Original languageEnglish
Pages (from-to)3729-3738
Number of pages10
JournalOncogene
Volume27
Issue number26
DOIs
Publication statusPublished - Jun 12 2008

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Heterografts
Cyclophosphamide
Colorectal Neoplasms
Ischemia
Mutation
Neoplasms
4-hydroxycyclophosphamide
DNA Mismatch Repair
Mutagenesis
ras Genes
Alkylating Agents
Therapeutics
Microvessels
Oncogenes
Cell Count
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts. / Shahrzad, S.; Shirasawa, S.; Sasazuki, Takehiko; Rak, J. W.; Coomber, B. L.

In: Oncogene, Vol. 27, No. 26, 12.06.2008, p. 3729-3738.

Research output: Contribution to journalArticle

Shahrzad, S. ; Shirasawa, S. ; Sasazuki, Takehiko ; Rak, J. W. ; Coomber, B. L. / Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts. In: Oncogene. 2008 ; Vol. 27, No. 26. pp. 3729-3738.
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