Hakam A, Yeatman TJ, Lu L, et al

Hakam A, Yeatman TJ, Lu L, et al. Small molecules that selectively inhibit the tyrosine kinase domain HS-10296 hydrochloride of IGF-1R without significant effect on the insulin receptor are under development [30, 41C47]. NVP-AEW541, a kinase inhibitor, has shown induction of apoptosis and cell cycle arrest in two CRC cell lines, HT29 and HCT-116, resulting HS-10296 hydrochloride in dose dependent inhibition of proliferation. Combining this agent with either 5-fluorouracil or cetuximab resulted in additive growth inhibition. NVP-AEW541 alone inhibited proliferation in primary cancer cell cultures of tumors from 8 patients with primary CRC [42]. Cyclolignan picropodophyllin (PPP), another IGF-1R kinase inhibitor, blocks IGF-1R activity, probably by inhibiting IGF-1R autophosphorylation at the substrate level, without affecting the insulin receptor [43]. PPP caused complete tumor regressions in xenografted and allografted mice [43]. Another class of IGF-1R kinase inhibitors are a family of bioisostere inhibitors, based on the structure of AG 538 a substrate-competitive inhibitor of IGF-IR. Catechol bioisosteres of AG 538 inhibit IGF-1R kinase activity and IGF-I induced IGF-1R autophosphorylation and block the formation of colonies in soft agar by cancer cells. IRS-1 phosphorylation and protein kinase B activation are inhibited when applied to intact cells [44]. 3.3 ANTISENSE AGENTS, DOMINANT NEGATIVE VARIANTS, AND OTHER AGENTS Resnicoff reported that C6 rat glioblastoma cells expressing an antisense IGF-1R RNA implanted for 24 h in the subcutaneous tissue of rats were able to elicit an anti-tumor response in the HS-10296 hydrochloride brain, leading to complete brain tumor regression and long-term survival of the rats [48]. Based on this, a human pilot safety and feasibility study used an antisense oligodeoxynucleotide directed against IGF-1R (IGF-1R/AS ODN) in patients with malignant astrocytoma. Autologous glioma cells collected at surgery were treated ex vivo with IGF-1R/AS ODN encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after 24-hours of in situ incubation. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including 2 complete responses [49]. Reiss et al [50] transfected a human colon cancer cell line with plasmids expressing the dominant negative mutant of IGF-1R, 486/STOP, which has a frameshift mutation resulting in a stop codon at residue 486. The stable expression of 486/STOP inhibited colony formation in soft agar as well as tumor growth in nude mice. Also, co-injection of cells expressing 486/STOP with wild-type tumor cells inhibited the growth of wild-type tumor cells secondary to a bystander effect [50]. IGF binding proteins (IGFBP-1 and IGFBP-3) are also being investigated as possible anticancer agents [51, 52]. 4.0 CONCLUSION The IGF system plays an important role in tumorigenesis and has been shown to be an absolute requirement for the establishment and maintenance of the HS-10296 hydrochloride transformed phenotype [53]. The effect of down-regulating the IGF system is more profound on cells growing in anchorage independent conditions as opposed to cells growing in a monolayer [54]. This may provide relative selectivity for agents that target this pathway for the treatment of cancer. Early clinical Hpt trials with agents targeting the IGF system are ongoing and will hopefully validate this pathway as a therapeutic target. Acknowledgments This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Bethesda, MD. CONFLICTS OF INTEREST: The authors have no conflicts of interest to report. Footnotes Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 6.0 REFERENCES 1. Yakar S, Leroith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models. Cytokine Growth Factor Rev. 2005;16:407C420. [PubMed] [Google Scholar] 2. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505C518. [PubMed] [Google Scholar] 3. Durai R, Yang W, Gupta S, et al. The role of the insulin-like growth factor system in colorectal HS-10296 hydrochloride cancer: review of current knowledge. Int J Colorectal Dis. 2005;20:203C220. [PubMed] [Google Scholar].