In Vitro Cytotoxicity Testing of Potential Anticancer Drugs

Powin, Garth

Abstract

The goal of the project is to identify from among compounds exhibiting activity in the signal transduction target screens in Projects 2, 3 and 4 those compounds that have significant growth inhibitory activity against tumor cells in vitro. A panel of 7 human tumor cell lines will be studied including three colon cell lines to represent one of the most chemoresistant human solid tumor types, and two leukemia cell lines representing a generally chemoresponsive human tumor type. The panel of cell lines includes all the human tumor xenografts used in the in vivo antitumor activity screen. Growth inhibitory activity will be measured using the soft agar colony formation assay. This assay is readily amenable to automation with high sample throughput, it is highly reproducible and gives a direct measure of cell growth with time. Statistical analysis of growth indices will be used to compare the effects of the agents among different cell lines. Agents exhibiting significant activity against any of the cell lines will be candidates for in vivo antitumor activity testing against the same cell lines and other human tumors in Project 6. Secondary studies will be conducted on agents showing only a partial in vivo response to identify pharmacodynamic and pharmacokinetic reasons for the discrepancy in activity. The information derived will be used by Project 1 to help design more active analogues of the compounds, for example with more desirable pharmacokinetic properties.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Research Project--Cooperative Agreements (U01)
• Project #: 1U01CA052995-01
• Application #: 3813290
• Support Year: 1
• Fiscal Year: 1990

Institution

• Name: Mayo Clinic, Rochester
• City: Rochester
• State: MN
• Country: United States
• Zip Code: 55905

Publications

Ihle, N T; Powis, G; Kopetz, S (2011) PI-3-Kinase inhibitors in colorectal cancer. Curr Cancer Drug Targets 11:190-8

Liu, Enbo; Knutzen, Christine A; Krauss, Sybille et al. (2011) Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 108:8680-5

Gwak, Ho-Shin; Shingu, Takashi; Chumbalkar, Vaibhav et al. (2011) Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer 128:787-96

Leone, Marilisa; Barile, Elisa; Vazquez, Jesus et al. (2010) NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH. Chem Biol Drug Des 76:10-6

Ihle, Nathan T; Powis, Garth (2010) The biological effects of isoform-specific PI3-kinase inhibition. Curr Opin Drug Discov Devel 13:41-9

Koul, Dimpy; Shen, Ruijun; Kim, Yong-Wan et al. (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559-69

Ihle, Nathan T; Powis, Garth (2010) Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol Aspects Med 31:135-44

Gaitonde, Supriya; De, Surya K; Tcherpakov, Marianna et al. (2009) BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. Pigment Cell Melanoma Res 22:187-95

Ihle, Nathan T; Lemos, Robert; Schwartz, David et al. (2009) Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther 8:94-100

Ihle, Nathan T; Lemos Jr, Robert; Wipf, Peter et al. (2009) Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143-50