Antitumour effect of combination treatment with Sabarubicin (MEN 10755) and cis-platin (DDP) in human lung tumour xenograft.

PURPOSE: Sabarubicin (MEN 10755), a new disaccaride anthracycline, has shown greater efficacy than Doxorubicin in a large panel of preclinical models and now it is in phase II clinical trials. Its promising antitumour activity promoted considerable interest to combine Sabarubicin with other antitumour agents. Thus, the purpose of this study was to evaluate in vitro cytotoxic effects and in vivo antitumour activities produced by the combination of Sabarubicin and cisplatin (DDP). METHODS: The antitumour effect of Sabarubicin and DDP association was investigated, in vitro and in vivo, in preclinical models of lung cancer i.e.: the non-small cell lung carcinoma (NSCLC) H460 and the small-cell lung carcinoma (SCLC) GLC4 in terms of synergism, additivity or antagonism in order to establish the best schedule for the combined treatment. Further, the correlation between antitumour activity and the pharmacokinetic parameters of the studied combination was also evaluated. RESULTS: The drug combination in vitro was in general more cytotoxic than the single drug alone, indicating the presence of a synergistic effect in both tumour cell lines. Also, in the xenograft experiments a superior antitumoral effect was observed when Sabarubicin was combined with DDP. The antitumour efficacy of Sabarubicin (6 mg/kg q4d x 5) combined with DDP (6 mg/kg q4d x 3) greatly depended on the schedule of administration. In H460 tumour line, the sequential combination was more effective than the simultaneous administration of the two agents, although the antitumour efficacy was not dependent on the sequence of combination. On the other hand, a strong sequence-dependent effect was observed when Sabarubicin was combined with DDP in SCLC, GLC4. In particular, the highest value of LCK = 6.7 was obtained when administration of DDP followed by 24 h that of Sabarubicin. Pharmacokinetics of Sabarubicin in combination with DDP was evaluated at 6 mg/kg for both drugs with different sequential schedule. The experimental data showed no evidence for pharmacokinetics drug-drug interaction. CONCLUSION: 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.

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.