Anticancer activity of a peptide combination in gastrointestinal cancers targeting multiple neuropeptide receptors.
A novel peptide combination consisting of four synthetic neuropeptide analogs of Vasoactive Intestinal Peptide (VIP), Bombesin, Substance P and Somatostatin has been found to have potent anticancer activity in vitro and in vivo. The receptors of these four neuropeptides are known to be over expressed in various cancers. We have found the presence of native neuropeptides in the culture supernatant of the primary tumor cells of human colon adenocarcinomas. It was further demonstrated by receptor-ligand assays that not only do these tumor cells synthesize and secrete four peptide hormones but also possess specific high affinity receptors on their surface. Screening a large panel of analogs to the four peptide hormones on tumor cell proliferation led to the identification of four cytotoxic analogs, the combination of which was code-named DRF7295. The design and synthesis of the peptide analogs have been described in this paper. In vitro anticancer activity of DRF7295 was studied in a large panel of human tumor cells. Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to be most sensitive to DRF7295 with moderate activity seen in glioblastoma, prostate, leukemia and those of oral cancer cells. Efficacy studies in xenograft models of colon and duodenum resulted in T/C% of less than 40%, which is indicative of strong tumor regressing potential of DRF7295 in gastrointestinal cancers. Acute and long-term toxicity studies as well as safety pharmacology studies conducted indicate the safety of the drug upon systemic administration with no significant adverse pharmacological effects.
Jaggi
Manu
M
Dabur Research Foundation, 22 Site IV, Sahibabad, Ghaziabad, 201010, India. jaggim@gmail.com
Prasad
Sudhanand
S
Singh
Anu T
AT
Praveen
R
R
Dutt
Sarjana
S
Mathur
Archana
A
Sharma
Rajan
R
Gupta
Neena
N
Ahuja
Rinku
R
Mukherjee
Rama
R
Burman
Anand C
AC
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives; D013373:Substance P / Q000031:analogs & derivatives; D018675:Toxicity Tests; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C534540:DRF 7295; D004338:Drug Combinations; D010455:Peptides; D018004:Receptors, Bombesin; D018040:Receptors, Neurokinin-1; D017481:Receptors, Somatostatin; D018005:Receptors, Vasoactive Intestinal Peptide; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D013004:Somatostatin; D001839:Bombesin