| First Author | Lee C | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 4 | Pages | 1564-72 |
| PubMed ID | 20145127 | Mgi Jnum | J:157609 |
| Mgi Id | MGI:4431271 | Doi | 10.1158/0008-5472.CAN-09-3228 |
| Citation | Lee C, et al. (2010) Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res 70(4):1564-72 |
| abstractText | Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reducing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling proteins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by expressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals. |
