neurokinin-a and Carcinoma

We demonstrate that neurokinin A (NKA) and substance P (SP) play a role in the proliferation of the estrogen receptor-negative (ER-) cell line MDA-MB-231, a human breast carcinoma expressing both NK-1 and NK-2 receptors. In vitro experiments showed that the specific receptor antagonists MEN 11,467 (NK-1) and nepadutant (MEN 11,420; NK-2) inhibited tumor cell proliferation, and blocked the stimulatory effect of SP and NKA. Anti-tumoral activity of NK-1 and NK-2 receptor antagonists was demonstrated in nude mice, measuring growth inhibition of MDA-MB-231 tumor cells xenografted s.c. and by using the hollow-fiber assay. In both systems a significant inhibition was found when compounds were administered at 5 mg/kg i.v. every day for 2 weeks. Results obtained from both these models suggest that the in vivo activity of NK-1 and NK-2 antagonists may be a result of a cytostatic effect rather than a cytotoxic effect. Our results suggest that the control of breast carcinoma (ER-) growth by tachykinin receptor antagonists may become a new form of targeted therapy for these human tumors.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cyclohexylamines; Female; Humans; Indoles; Mice; Mice, Nude; Molecular Structure; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptides, Cyclic; Receptors, Neurokinin-1; Receptors, Neurokinin-2; RNA, Messenger; Substance P; Xenograft Model Antitumor Assays