Resultados de fase I que apareceran en la publicación de Noviembre 2010 de la British Journal of Pharmacology .Volume 161, Issue 5, pages 1099–1110, November 2010 .
Se trata del 5 º Farmaco de Pharma Mar que esta en ensayos clinicos y que fue el ultimo en iniciarlos ... con los resultados que ahora se publican es garantia de continuidad :
PM01183 ha finalizado su primer ensayo de fase I en pacientes con tumores sólidos refractarios. El reclutamiento finalizó en septiembre de 2010 con 31 pacientes tratados y se ha encontrado una dosis recomendada segura y eficaz para el próximo inicio de la fase II. La dosis ha sido segura y bien tolerada observándose gran eficacia anti-tumoral
en diferentes tipos tumorales.
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BACKGROUND AND PURPOSE :
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that is currently in phase I clinical development for the treatment of solid tumours. In this study we have characterized the interactions of PM01183 with selected DNA molecules of defined sequence and its in vitro and in vivo cytotoxicity.
EXPERIMENTAL APPROACH :
DNA binding characteristics of PM01183 were studied using electrophoretic mobility shift assays, fluorescence-based melting kinetic experiments and computational modelling methods. Its mechanism of action was investigated using flow cytometry, Western blot analysis and fluorescent microscopy. In vitro anti-tumour activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the in vivo activity utilized several human cancer models.
KEY RESULTS :
Electrophoretic mobility shift assays demonstrated that PM01183 bound to DNA. Fluorescence-based thermal denaturation experiments showed that the most favourable DNA triplets providing a central guanine for covalent adduct formation are A GC, C GG, A GG and T GG. These binding preferences could be rationalized using molecular modelling. PM01183−DNA adducts in living cells give rise to double-strand breaks, triggering S-phase accumulation and apoptosis. The potent cytotoxic activity of PM01183 was ascertained in a 23-cell line panel with a mean GI50 value of 2.7 nM. In four murine xenograft models of human cancer, PM01183 inhibited tumour growth significantly with no weight loss of treated animals.
CONCLUSIONS AND IMPLICATIONS :
PM01183 is shown to bind to selected DNA sequences and promoted apoptosis by inducing double-strand breaks at nanomolar concentrations. The potent anti-tumour activity of PM01183 in several murine models of human cancer supports its development as a novel anti-neoplastic agent.