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Clin Cancer Res. 2010 Nov 15;16(22):5436-46. doi: 10.1158/1078-0432.CCR-10-2054. Epub 2010 Oct 13.

The insulin-like growth factor I receptor/insulin receptor tyrosine kinase inhibitor PQIP exhibits enhanced antitumor effects in combination with chemotherapy against colorectal cancer models.

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1
Developmental Therapeutic Program, University of Colorado, 12801 E. 17th Avenue, Aurora, CO 80045, USA.

Abstract

PURPOSE:

There is growing evidence implicating the importance of the insulin-like growth factor (IGF) pathway in colorectal cancer based upon the results of population studies and preclinical experiments. However, the combination of an IGF-I receptor (IGF-IR) inhibitor with standard colorectal cancer chemotherapies has not yet been evaluated. In this study, we investigated the interaction between PQIP, the dual IGF-IR/insulin receptor tyrosine kinase inhibitor, and standard chemotherapies in colorectal cancer cell line models.

EXPERIMENTAL DESIGN:

The antiproliferative effects of PQIP, as a single agent and in combination with 5-fluorouracil, oxaliplatin, or SN38, were analyzed against four colorectal cancer cell lines. Downstream effector proteins, apoptosis, and cell cycle were also assessed in the combination of PQIP and SN-38. Lastly, the efficacy of OSI-906 (a derivative of PQIP) combined with irinotecan was further tested using a human colorectal cancer xenograft model.

RESULTS:

Treatment with the combination of PQIP and each of three chemotherapies resulted in an enhanced decrease in proliferation of all four colorectal cancer cell lines compared with single-agent treatment. This inhibition was not associated with a significant induction of apoptosis, but was accompanied by cell cycle arrest and changes in phosphorylation of Akt. Interestingly, antitumor activity between PQIP and SN-38 in vitro was also reflected in the human colorectal cancer xenograft model.

CONCLUSIONS:

Combination treatment with PQIP, the dual IGF-IR/insulin receptor tyrosine kinase inhibitor, and standard colorectal cancer chemotherapy resulted in enhanced antiproliferative effects against colorectal cancer cell line models, providing a scientific rationale for the testing of OSI-906 and standard colorectal cancer treatment regimens.

PMID:
20943761
PMCID:
PMC3119523
DOI:
10.1158/1078-0432.CCR-10-2054
[Indexed for MEDLINE]
Free PMC Article
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