Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft.
Astrocytes harbour functional receptors to many neurotransmitters, including substance P (SP), an undecapeptide belonging to the tachykinin family of peptide transmitters. SP activates malignant glial cells to induce cytokine release and proliferation, both responses being relevant for tumour progression. In tumours developed in nude mice transplanted subcutaneously (s.c.) to U373 MG human glioma cells, the presence of SP was observed at immunohistochemistry. Although the administration of exogenous SP did not significantly affect the size or development of U373 MG xenograft, a role of SP in supporting glioma progression in vivo was highlighted by the tumour growth inhibition induced by highly specific and selective human tachykinin NK1 receptor antagonists (MEN 11467 and MEN 11149). The anti-tumour activity of MEN 11467 was observed both with s.c. or intravenous treatments and was partially reverted by the concomitant administration of exogenous SP. Doxorubicin did not show any activity in controlling U373 MG growth in this in vivo model. A novel therapeutic approach to treat malignant gliomas with tachykinin NK1 receptor antagonists is suggested by these findings.
Palma
C
C
Menarini Ricerche S.p.A., Department of Pharmacology, Pomezia, RM, Italy.
Bigioni
M
M
Irrissuto
C
C
Nardelli
F
F
Maggi
C A
CA
Manzini
S
S
D000818:Animals; D002455:Cell Division; D003514:Cyclohexylamines / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D003514:Cyclohexylamines; D016207:Cytokines; D007211:Indoles; C111883:MEN 11149; C121095:MEN 11467; D009281:Naphthalenes; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P