Nuevas estrategias en el tratamiento de la leucemia mieloide crónica / New strategies in the treatment of chronic myeloid leukemia

En los últimos años se han propuesto nuevos modelos terapéuticos para ser utilizados en pacientes con leucemia mieloide crónica (LMC) resistentes o intolerantes al Imatinib. La mayor parte de estos modelos están basados en intervenciones sobre sitios específicos del sistema de transmisión de señales que la célula utiliza para hacer llegar información al núcleo. Una de las estrategias incorporadas es el uso de inhibidores de la farnesiltransferasa y ya se han identificado productos terapéuticos factibles de ser utilizados por vía oral, debido al pequeño tamaño de sus moléculas. Actualmente hay 4 inhibidores en fases más avanzadas, fundamentalmente el R115777 (zarnestra, tipifarnib). La búsqueda de otros modelos de tratamiento dio lugar a la aparición de nuevas moléculas que pudieran ser utilizadas para tratar los casos de resistencia o intolerancia al Imatinib, entre estas el Desatinib y el Dilotinib. Otra molécula en fase de experimentación en casos de resistencia al Imatinib es la conocida actualmente como .PKC 412 (N benzil-estauroporina), CGP41251 que es un potente inhibidor selectivo de las isoformas de la proteincinasa C. El desarrollo de la terapéutica molecular ha avanzado rápidamente y su aplicación en la LMC ha logrado resultados muy positivos que se deben incrementar con la incorporación de los nuevos medicamentos en estudio y de aquellos que seguramente deben aparecer en un futuro.

New therapeutic models have been recommended in the last years to be used in patients with chronic myeloid leukemia (CML) resistant or intolerant to Imatinib. Most of the models are based on interventions on specific sites of the signal transmission system that the cells used to send information to the nucleus. One of the strategies that has been incorporated is the use of farnesyl transferase inhibitors. Therapeutic products that may be administered by oral route, due to the small size of their molecules, have already been identified. At present, there are 4 inhibitors in more advanced stages, mainly the R115777 (zarnestra, tipifarnib). The search for other tretament models gave rise to the appearance of new molecules that may be used to treat the cases of resistance or intolerance to Imatinib, such as Desatinib and Dilotinib. Other molecule under experimentation phase is that currently known as PKC 412 (N-benzoylstaurosporine), CGP41251 that is a powerful selective inhibitor of the protein kinase C isoforms . The development of the molecular therapeutics has advanced rapidly and its application to CML has attained very positive results that should increase with the incorporation of the new drugs under study and of those that will certainly emerge in the future.

The Effect of Farnesyl Transferase Inhibitor on the Proliferation of Vascular Smooth Muscle Cells and Neointima Formation

BACKGROUND AND OBJECTIVES: We tested the hypothesis that prolonged oral administration of farnesyl transferase inhibitor (FTI, LB42908a, MW=604, LG chemical, Korea) inhibits the proliferation and neointimal thickening of smooth muscle cells (SMC) in a rat carotid injury model. MATERIALS AND METHODS: Cultured rat aortic vascular SMCs were exposed to sequential concentrations of FTI, and the proliferation inhibition analyzed using the MTT assay. In the rat carotid injury model, the FTI, at 3 dose levels (low-dose;10mg/kg, bid;mid-dose;50mg/kg, bid;high-dose;100 mg/kg, bid), or as a placebo, was administered orally, twice a day for 14 days, starting from 30 minutes before injury, until sacrifice. The histo-morphometric analysis was performed. The immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) was performed for 3 days. RESULTS: FTI inhibited the PDGF or FBS-induced cellular proliferations in a dose dependently manner. In the rat carotid artery balloon injury model, the mean neointimal area was significantly less in the mid-dose group than in the placebo and low-dose groups (control:0.35+/-0.04mm2, low-dose:0.23+/-0.04mm2 and mid-dose:0.19+/-0.04mm2, p<0.05), and the mean ratio of the neointima to medial areas were significantly less in the mid-dose group than in the placebo and low dose group (placebo:3.02+/-0.34, low-dose:2.24+/-0.54 and mid-dose:1.47+/-0.31, p<0.05). The labeling index of the PCNA was significantly less in the mid-dose group than in the placebo and low-dose groups (control:71+/-9, low-dose:73+/-9, mid-dose:54+/-14 and high-dose:53+/-9, p<0.05). CONCLUSION: The FTI inhibits SMC proliferation in a dose dependent manner. The prolonged oral administration of FTI, for 14 days, is effective in reducing neointimal hyperplasia in the rat carotid balloon injury model.

Inhibition of Corneal Angiogenesis by a Farnesyl Transferase Inhibitor

Farnesyl transferase inhibitor(FTI) disrupt farnesylation of ras protein and thus, suppress tumor growth in vivo. The ras oncogene is thought to contribute to tumor development directly by promoting tumor cell proliferation and indirectly by stimulating vascular endothelial growth from Cinnamomum Cassia Blume(CB2`-ph) interferes with angiogenesis, we studied the effect of CB2`-ph on rabbit corneal angiogenesis induced by VEGF. A hygrogel disk containing 250ng of VEGF was implated intrastromally in the superior cornea of 16 NZW rabbit eyes. All eyes received a second intrastromal disk, randomized to contain either 40 micro gram of CB2`-ph(n=8) or phosphate-buffered saline(PBS)(n=8). Both disks were positioned side-by-side, 1.2mm from the superior limbus. Each eye was examined daily by two masked observers and assigned an angiogenesis score based on number and length of new blood vessels. At 3, 5 and 7 days postimplantation of VEGF disks, eyes treated with CB2`=ph showed mean angiogenesis score of 2.0 +/- 1.7, 13.4 +/- 6.6 and 23.8 +/- 11.3, respectively, while PBS=treated controls scored 8.6 +/- 4.4, 30.3 +/- 20.8 and 52.2 +/- 26.9, respectively(p<0.05, Wilcoxon signed rank test). In a rabbit corneal pocket assay, CB2`-ph appears to be effective on VEGF-induced corneal angiogenesusis in the model.

Inhibition of Basic Fibroblast Growth Factor Induced Corneal Angiogenesis by a Farnesyl Transferase Inhibitor

Farnesyl transferase inhibitors(FTI) disrupt fanesylation of ras protein and thus, suppress tumor growth in vivo, To determine whether FTI extracted from Cinnamomum Cassia Blume(CB2`-ph) interferes with angiogenesis, we studied the effect of CB2`-ph on rabbit corneal angiogenesis induced by basic fibroblast growth factor(bFGF). A hydrogel disk containing 1000ng of bFGF was implanted intrastromally in the superior cornea of 12 NZW rabbit eyes. All eyes received a second intrastromal disk, randomized to contain either 40 micro gram of CB2`-ph(n=6) or phosphate-buffered saline(PBS)(n=6). Both disks were positioned side-by-side, 1.2mm from the superior limbus. Each eye was examined daily by two masked of new blood vessels. At 3, 5, and 7 days postimplantation of bFGF disks, eyes treated with CB2`-ph showed mean angiogenesis score of 6.0 +/- 4.8, 25.6 +/- 23.9 and 38.1 +/- 28.3, respectively, while PBS-treated controls scored 10.4 +/- 9.2, 27.2 +/- 16.7, and 39.0 +/- 22.8, respectively(p>0.4, Wilcoxon signed rank test). In a rabbit corneal pocket assay, CB2`-ph appears to be ineffective against bFGF-induced corneal angiogenesis in the model.