Zalypsis , Irvalec , PM1183 y PM060184 son los Farmacos de Nueva generacion de Pharma Mar , algunos de ellos son Analogos de Viejos conocidos por lo que les imprime mayor potencial ... un antes y un despues en la I+D .
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MADRID, 7 Abr. (EUROPA PRESS) -
PharmaMar, compañía biofarmacéutica del Grupo Zeltia, ha presentado los resultados obtenidos con los antitumorales de origen marino 'Irvalec' y 'PM01183', en los que se ha confirmado el efecto del primero sobre la membrana plasmática y la actividad del segundo sobre las células resistentes al platino y su capacidad de disminuir la actividad del sistema NER (Nucleotide Excision Repair, por sus siglas en inglés).
Las conclusiones, expuestas durante la Reunión Anual de la American Association for Cancer Research (AACR), que se acaba de celebrar en Orlando (Florida), de 'PM01183' muestran las propiedades combinatorias favorables con la mayoría de los compuestos con los que se han realizado los ensayos, "habiendo fuertes sinergias con irinotecan, paclitaxel y dacarbazine".
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Conclusiones de las Tres Presentaciones :
PM1183 :
Purpose: PM01183 is a novel marine-derived covalent DNA binder with structural similarity to trabectedin, but with different pharmacokinetics as indicated by early clinical studies. Resistance to DNA alkylators, and platinum regimens in particular, is often accompanied by increased nucleotide excision repair (NER) activity. We here characterize the repair of PM01183 and trabectedin and determine the activity of the two agents toward cells with acquired platinum resistance.
Experimental Design: The activity of PM01183 and trabectedin toward platinum-resistant ovarian or colon cancer cells was determined by the MTT viability assay. NER activities were determined by unscheduled DNA synthesis (DNA repair synthesis) and adduct removal using adduct-specific antibodies. The activity of PM01183 and cisplatin combinations was evaluated by Chou and Talalay analysis.
Results: All cisplatin- or oxaliplatin-resistant cell lines showed unchanged or enhanced sensitivity to PM01183 and trabectedin, whatever their NER levels. Neither compound was repaired by NER, but both were able to interfere with the NER process thereby attenuating the repair of bona fide NER substrates. Accordingly, combinations of PM01183 and cisplatin were at least additive toward both parental and cisplatin-resistant ovarian cancer cells.
Conclusions: We here show that PM01183 has activity toward cells with acquired platinum resistance. PM01183 is not repaired by NER, but is able to attenuate the NER process. Accordingly, combinations of PM01183 and cisplatin are at least additive toward both parental and cisplatin-resistant carcinoma cells. These data provide a mechanistic basis to support clinical trials of PM01183 in combination with cisplatin toward both platinum-sensitive and -resistant tumors.
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PM1183 :
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. PM01183 displays significant antitumor activity in several murine models of human cancer. PM01183 is currently in phase I/II clinical development for cancer treatment. Nonclinical combination studies are increasingly relevant during the development of any anticancer compound. As such, PM01183 was assayed in combination (two-drugs) with representatives of alkylating agents (dacarbazine, temozolomide and cisplatin), antimetabolites (5-FU and gemcitabine), DNA-topoisomerase inhibitors (irinotecan and doxorubicin) and tubulin binding agents (paclitaxel and vinorelbine). Different models were used depending on the combination explored: STS (HT1080) for dacarbazine; glioma (U-87 MG) for temozolomide; gastric (HGC-27) for cisplatin and 5-FU; pancreas (SW1990) for gemcitabine; colon (HT-29) and NSCLC (H460) for irinotecan; and ovarian (A2780) for doxorubicin, paclitaxel and vinorelbine. Athymic nu/nu mice bearing tumors (ca. 150 mm3) were randomly allocated to 13 treatment groups: i) placebo; ii) PM01183 at 4 different dose levels, namely MTD (0.180 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; iii) Compound to be combined, at 4 different dose levels MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, iv) PM01183 plus the combined compound, administered with the combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of MTD ratios. The antitumor activity was followed by T/C, (change in tumor volume for each treated -T- and placebo -C- groups during placebo-treated survival period). Then, the fraction affected (Fa) by the treatment was calculated (1-T/C) and, the combination index (CI) by the CI-isobol method determined. Synergism (CI ≤ 1 at Fa > 0.8) was recorded when PM01183 was combined with dacarbazine (HT1080), cisplatin (HGC-27), 5-fluororacil (HGC-27), gemcitabine (SW1990), irinotecan (H460), doxorubicin (A2780), paclitaxel (A2780) and vinorelbine (A2780).
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Irvalec :
Irvalec® (PM02734, elisidepsin) is a marine-derived cytotoxic depsipeptide currently undergoing phase II clinical studies. Irvalec® inserts and self-organize in the plasma membrane of tumor cells, rapidly inducing loss of membrane integrity, cell permeabilization, an increase in membrane ion conductance and calcium movement across the membrane, resulting in a very rapid necrotic cell death.
By continuous exposure of lung A549 and colon HCT-116 human tumor cells to stepwise, increasing concentratrions of Irvalec®, we established two resistant subclones of these cell lines, A549-Irv and HCT-116-Irv. In dose-response cytotoxicity assays, A549-Irv and HCT-116-Irv cells showed GI50 values of 32 and >50 μM, respectively, representing resistance indexes of 8.5 and >10.8 as compared to their wt counterparts.
Resistant cells did not show any of the morphological and physiological responses to Irvalec® observed in wt cells. No significant cross-resistance to other standard antitumor compounds was detected. Interestingly, A549-Irv but not HCT-116-Irv cells, were more sensitive to tubulin interacting agents, including taxanes and vinca alkaloids, than the wt cells, suggesting a role for the cytoskeleton in the mechanism of the acquired resistance to Irvalec®. Analysis of protein expression in wt and resistant cells showed a significant decrease of certain membrane or membrane-associated proteins in resistant cells; cytosolic proteins were virtually unaffected. Among the proteins whose expression was significantly decreased in resistant cells, E-cadherin was the most outstanding, being its expression nearly abolished in A549-Irv resistant cells. These results indicate that changes in the cell membrane composition of the resistant cells occurred during the process of establishment, that may involve trafficking of proteins from the golgi to the membrane or protein insertion and/or stability in the lipid bilayer.