human neuroblastoma: New therapeutic strategies suggested by experimental models

Neuroblastoma (NB) is the most common extracranial metastatic solid tumour of childhood. In the last five years the survival of patients affected by the diffuse forms of the disease did not substantially improve, in spite of more sophisticated diagnostic procedures and high dose (HD) therapeutic regimens followed by autologous bone marrow (BM) rescue. Recombinant cytokines (rCK), such as GM-CSF, Interferons (IFNs) and other biological response modifiers (BRMs) are new therapeutic tools some of which are already in clinical trials. BRM and rCK are used as single agents either to reduce the hypoplasia induced by HD regimens or to overcome tumor resistance to 'classic' anti-neoplastic drugs. Very little information is available on experimental trials aimed to improve the therapeutic response by combining the various rCKs and/or BRMs. In the last few years we developed therapeutic experimental models designed to: (a) combine rCKs and BRMs in a way that significantly enhance their antitumor effect. (b) overcome the problem of BM aplasia induced by HD regimens by exploiting the activity of a peptide produced by neural sensory cells. Three major findings have been achieved: (a) γ-IFN and TNF synergize in vitro in inducing proliferation arrest and differentiation of NB cells toward a neuronal phenotype. (b) γ-IFN and retinoic acid synergize in vivo in reducing the growth of the same NB cells grafted in nude mice. (c) a 10-11 Substance P analogue has been synthesized that stimulates the growth of BM progenitor cells, which significantly reducing the leukopenia induced in mice by total body irradiation, cyclophosphamide or 5-fluoro-uracyl. We summarize here the results related to (a), while all findings related to (b) and (c) have previously been reported^1-4.