Increased gastrin-releasing peptide (GRP) receptor expression in tumour cells confers sensitivity to [Arg6,D-Trp7,9,NmePhe8]-substance P (6-11)-induced growth inhibition.
[Arg(6),D-Trp(7,9),N(me)Phe(8)]-substance P (6-11) (SP-G) is a novel anticancer agent that has recently completed phase I clinical trials. SP-G inhibits mitogenic neuropeptide signal transduction and small cell lung cancer (SCLC) cell growth in vitro and in vivo. Using the SCLC cell line series GLC14, 16 and 19, derived from a single patient during the clinical course of their disease and the development of chemoresistance, it is shown that there was an increase in responsiveness to neuropeptides. This was paralleled by an increased sensitivity to SP-G. In a selected panel of tumour cell lines (SCLC, non-SCLC, ovarian, colorectal and pancreatic), the expression of the mitogenic neuropeptide receptors for vasopressin, gastrin-releasing peptide (GRP), bradykinin and gastrin was examined, and their sensitivity to SP-G tested in vitro and in vivo. The tumour cell lines displayed a range of sensitivity to SP-G (IC(50) values from 10.5 to 119 microM). The expression of the GRP receptor measured by reverse transcriptase-polymerase chain reaction, correlated significantly with growth inhibition by SP-G. Moreover, introduction of the GRP receptor into rat-1A fibroblasts markedly increased their sensitivity to SP-G. The measurement of receptor expression from biopsy samples by polymerase chain reaction could provide a suitable diagnostic test to predict efficacy to SP-G clinically. This strategy would be of potential benefit in neuropeptide receptor-expressing tumours in addition to SCLC, and in tumours that are relatively resistant to conventional chemotherapy.
Waters
C M
CM
Lung Inflammatory Group, Centre for Inflammation Research, University of Edinburgh Medical School, Hugh Robson Building, George Square, UK.
MacKinnon
A C
AC
Cummings
J
J
Tufail-Hanif
U
U
Jodrell
D
D
Haslett
C
C
Sethi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001920:Bradykinin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014667:Vasopressins / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D010446:Peptide Fragments; D018004:Receptors, Bombesin; D018013:Receptors, Neuropeptide; D014667:Vasopressins; C046958:substance P (6-11), Arg(6)-Trp(7,9)-Me-Phe(8)-; D013373:Substance P; D019886:Gastrin-Releasing Peptide; D001920:Bradykinin; D002118:Calcium