Malignant astrocytomas or glioblastomas represent the most common type of primary brain tumour in adults (Salcman and Kaplan, 1986;Hochberg and Pruitt, 1987). High-grade malignant gliomas are inevitably lethal neoplasms and the median survival of patients treated with standard cytoreductive surgery and postoperative radiotherapy is in the range of 1 year. Likewise chemotherapy is of limited effectiveness in the treatment of these tumours and other therapeutic approaches must be explored. Glioblastomas are sensitive to several hormones and growth factors. The presence of receptors for epidermal growth factor, platelet-derived growth factor, insulin-like growth factor-I/II as well as for glucocorticoid, androstenedione and progesterone in malignant gliomas, has been described (Shapiro et al, 1995). Recently, neurotransmitters/neuropeptides have also been found to regulate astrocytoma growth (Sharif, 1998).Substance P (SP), an undecapeptide of the tachykinin family of neuropeptides, is released both in the central and peripheral nervous systems, playing a well established role in neuronal transmission, vasodilatation and motor responses (Maggi et al, 1993). Tachykinins exert their actions through activation of G-protein coupled receptors, labelled NK 1 , NK 2 , NK 3 ; SP is the preferential endogenous ligand for the tachykinin NK 1 receptor (Maggi et al, 1993;Otsuka and Toshioka, 1993). In various astrocytic/glial brain tumour-derived cell lines, the presence of tachykinin NK 1 receptor strictly correlates with the effect of SP and/or NKA in increasing DNA synthesis and cellular proliferation Sharif et al, 1996;Palma et al, 1999a). In addition, SP can control many other glial responses such as taurine release, secretion of various cytokines (e.g. interleukin (IL)-6, IL-8, transforming growth factor-β, leukaemia inhibitory factor, granulocyte-macrophage colony stimulating factor) which are thought to be relevant for glioma progression (Gitter et al, 1994;Palma et al, 1995;Palma and Manzini, 1998). In a large number of these studies, the human astrocytoma grade III U373 MG cell line, which expresses a high level of functional tachykinin NK 1 receptor (Lee et al, 1992;Palma et al, 1999b) but not tachykinin NK 2 or NK 3 receptors (Heuillet et al, 1993), were used.The role of SP in glioma activities may be ascribed to a pathological use of normal signal transduction pathways occurring in reactive astrocytes. In fact, SP activates phospholipase C and stimulates the release of IL-6 and prostaglandin E 2 from human fetal astrocytes in culture (Palma et al, 1997), and there is evidence for an up-regulation of this receptor by reactive proliferating astrocytes after transection of the optic nerve (Mantyh et al, 1989). Moreover, SP-immunoreactive astrocytes have been observed in multiple sclerosis plaques (Kostyk et al, 1989) and in the forebrains of human infants (Michel et al, 1986). Interestingly, the involvement of tachykinin NK 1 receptor and SP in glioma progression was not only supported by the functional in vitro stud...

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.

These preclinical results indicate the potential for a strong antitumour activity in lung tumours of the combination Sabarubicin and DDP. In particular, in SCLC the best response should be given by a sequence with administration of Sabarubicin followed 24 h later by that of DDP. Clinical trials based on these results are ongoing.