Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas.

Abstract

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.

• Authors: Anu T Singh, Manu Jaggi, Sudhanand Prasad, Sarjana Dutt, Gurvinder Singh, Kakali Datta, Praveen Rajendran, Vinod K Sanna, Rama Mukherjee, Anand C Burman
• Journal: Investigational new drugs (Invest New Drugs) Vol. 26 Issue 6 Pg. 505-16 (Dec 2008) ISSN: 0167-6997 [Print] United States
• PMID: 18322652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DRF 7295
• Drug Combinations
• Peptides
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• Epidermal Growth Factor
• Cyclic AMP
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Caspase 3

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (drug effects, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP (metabolism)
• Down-Regulation (drug effects)
• Drug Combinations
• Drug Screening Assays, Antitumor (methods)
• Epidermal Growth Factor (drug effects, metabolism)
• Gastrointestinal Neoplasms (drug therapy, physiopathology)
• Humans
• Mitogen-Activated Protein Kinase 1 (drug effects, metabolism)
• Mitogen-Activated Protein Kinase 3 (drug effects, metabolism)
• Peptides (pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (drug effects, metabolism)