NEUROKININ ANTAGONISTS

Is there a use for neurokinin antagonists?

Is there a use for neurokinin antagonists?

Proposal summary

I will research on neurokinin antagonists which will entensively look into various aspects of disease and its medical and social impacts. Following is the brief overview of the research.

It has also been demonstrated that the activation of the NK-1 receptor by SP induces mitogenesis in several melanoma cell lines [9-11] and in other tumor cell lines [12-20]. In addition, it is known that SP is a main mediator of capillary vessel growth in vivo and of the proliferation of cultured endothelial cells in vitro, and that SP also induces neoangiogenesis . Moreover, the active migration of tumor cells, a crucial requirement for invasion and metastasis development, is regulated by SP signals .

Melanoma is a neoplasm originating from melanocytes, which are derived from the neural crest. It represents 1% of cancers and it accounts for approximately 65% of skin cancer deaths. Melanoma now anecdotes for roughly 4% of all cancers diagnosed in the joined States . Presently, primary cutaneous malignant melanoma can be effectively managed with surgical treatment, obtaining high survival rates after five years follow-up. However, survival dramatically decreases in stages III and IV of this tumor. In these phases, an productive remedy does not exist. The last two decades have glimpsed no significant progress in expanding the survival of patients with distant metastases, regardless of multiple tests of cytotoxic chemotherapy agents. Therefore, there is an urgent need to improve therapy in melanoma patients. Substance P (SP) is an undecapeptide that belongs to the tachykinin family of peptides. It is known that SP, neurokinin A (NKA), neuropeptide K and neuropeptide Gamma (the two latter elongated forms of NKA) are derived from the preprotachykinin A gene, whereas neurokinin B (NKB) is derived from the preprotachykinin B gene. The biological actions of SP, NKA and NKB are mediated by three receptors, named neurokinin (NK)-1, NK-2 and NK-3; the NK-1 receptor showing preferential affinity for SP. After binding to the NK-1 receptor, SP regulates many biological functions [2,3] and this neuropeptide has also been implicated in neurogenic inflammation, pain and depression as well as in tumor cell proliferation, neoangiogenesis and metastasis [5,6]. In addition, the expression of SP in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical (dysplastic) nevi, and spindle and epithelioid cell (Spitz) nevi has been described, but it was not detected in any acquired benign melanocytic nevi . Moreover, it was recently reported that human malignant melanoma cell lines and melanoma samples express NK-1 receptors .

The NK-1 receptor antagonist L-733,060 (a piperidine derivative) showed a high affinity for the human NK-1 receptor in vitro . We have also demonstrated that L-733,060 shows antitumor activity against human malignant melanoma cell lines and against neuroblastoma, glioma, retinoblastoma, pancreas, larynx, gastric and colon carcinoma cell lines [10,15,16,19,20]. Furthermore, it has been recently reported that the NK-1 receptor antagonist aprepitant (a morpholine derivative) is a broad spectrum antitumor drug and exerts an antitumor action against ...