Research in my laboratory is focused on developing the molecular basis of combinatorial therapeutic strategies involving radiation, chemotherapeutic agents and small molecule inhibitors. We have initiated two programs that address tumor resistance to radiation and/or chemotherapy: (1) Pre-clinical evaluation of chemotherapeutic agents and small molecule inhibitors as potential radio-sensitizers (2) Basic research program to analyze the effect of small molecule inhibitors on Cycloocygenase-2 (COX-2) expression induced by radiation and chemotherapeutic agents in lung carcinoma cells. We are currently investigating two lead chemotherapeutic agents, oxaliplatin and docetaxel in combination with radiation. Our objective is to evaluate the potential of oxaliplatin as a radiation sensitizer and determine the appropriate dose and schedule of oxaliplatin when applied during and/or following a course of docetaxel and radiation therapy in pre-clinical human lung carcinoma model. We are also investigating the effect of several small molecule inhibitors (Terceva, Iressa, Flavopiridol, BMS387032) as potential radio-sensitizers and their effect on COX-2 expression. Increase in COX-2 expression is associated with tumor progression and plays a critical role in the acquisition of an invasive and metastatic phenotype that may leads to the resistance to radiation and chemotherapy. Ionizing radiation and chemotherapeutic agents including docetaxel have been shown to induce COX-2 expression in lung carcinoma cells. In our current study we are using a novel class of compounds known as cyclin dependent kinase inhibitors (cdk-I) to arrest the signaling pathways that induce COX-2 gene expression in response to (i) radiation, (ii) chemotherapy and (iii) cytokines. A primary objective of this investigation is to elucidate the role of cdk2 in the transcriptional activation of COX-2 gene expression. A second component of this study will analyze cellular and tissue proteomic patterns in response to the combined treatment of chemo-radiation and cdk-inhibitors. Comparison of the proteomic profiles between the different treatments may identify a novel characteristic proteomic pattern especially in the radio-and chemo-resistant samples. These proteomic patterns are of special interest to differentiate the drug and/or radiation induced markers.
RESEARCH INTERESTS
Role of Cycloxygenase-2 in radiation and chemo-resistance.
Role of small molecule inhibitors as radio-sensitizers
RECENT PUBLICATIONS
Mukhopadhyay P, Ali MA, Nandi A, Carreon P, Choy H and Saha D, "The Cyclin Dependent Kinase 2 Inhibitor Downregulates Interleukin 1-Beta Mediated Induction of Cyclooxygenase 2 Expression in Human Lung Carcinoma Cells" Accepted for publication in Cancer Research, In Press
Saha D, Sekhar M, Cao C, Morrow JD, Choy H and Freeman ML, "The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity" Cancer Research, 63:6920-6927, October 2003
Kim JC, Ali MA, Nandi A, Mukhopadhyay P, Choy H, Cao C and Saha D, "Correlation of HER1/EGFR expression and degree of radiosensitizing effect of the HER1/EGFR-tyrosine kinase inhibitor erlotinib" Indian Journal of Biochemistry and Biophysics, In Press:In Press
Kim JC, Saha D, Cao C and Choy H, "Enhancement of radiation effects by combined docetaxel and flavopiridol treatment in lung cancer cells." Radiotherapy and Oncology, 71:213-221, May 2004
Saha D, Pyo H and Choy H, "COX-2 inhibitor as a radiation enhancer: new strategies for the treatment of lung cancer." American Journal of Clinical Oncology, 26:S70-S74, August 2003
SIGNIFICANT PUBLICATIONS
Saha D, Datta PK and Beauchamp RD, "Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4." Journal of Biological Chemistry, 276:29531-29537, August 2001
Saha D, Datta PK, Sheng H, Morrow JD, Wada M, Moses HL and Beauchamp RD, "Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells." Neoplasia, 6:508-517, December 1999
Kim JC, Kim JS, Saha D, Cao Q, Shyr Y and Choy H, "Potential radiation-sensitizing effect of semisynthetic epothilone B in human lung cancer cells." Radiotherapy and Oncology, 68:305-313, September 2003
Berger DH, Feng XH, Yao J, Saha D, Beauchamp RD, Lin X, "Resistance to transforming growth factor-beta occurs in the presence of normal Smad activation." Surgery, 132:310-316, August 2002
Saha D and Choy H, "Potential for combined modality therapy of cyclooxygenase inhibitors and radiation." Prog Exp Tumor Res, 37:193-209, 2003
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