Niveles de topotecan en el vitreo luego de la administración periocular en conejos / Vitreous topotecan levels after periocular administration in rabbits

Estudiar los niveles de topotecan total y lactona en el vitreo luego de la administración periocular en un modelo animal. Material y métodos: Se administró 1 mg de topotecan periocular en ambos ojos a 9 conejos sin retinoblastoma y se midieron niveles en el vitreo a las 0.25, 0.5, 1, 2, 4 y 24 horas. Se midieron niveles plasmáticos en 2 animales a las 2 horas. Se midió topotecan total y lactona por HPLC. Todos los animales fueron enucleados al completar el experimento y los ojos fueron examinados patológicamente para evalur toxicidad. Resultados: Tanto el topotecan total como la lactona alcanzaron niveles en el vitreo, mostrando un pico a los 30 minutos de la administración periocular. Los niveles medios en el pico fueron de 158 ng/ml para el topotecan total y 122 ng/ml para el topotecan lactona decayendo con una vida media de 2.44 hs. y 2.8 hs. para el topotecan total y lactona respectivamente. Se encontraron bajos niveles plasmáticos en los 2 animales estudiados a las 2 hs. de la administración de topotecan periocular ((32.0 ng7ml). No se evidencio toxicidad significativa. Conclusiones: En este estudio preliminar, el topotecan mostro lograr pernetrar al vitreo luego de la administración periocular a concentraciones potencialmente tumoricidas. Nuestro grupo proseguirá con estudios más detallados para evaluar su comportamiento famacocinético con el fin de utilizarlo potencialmente en paciente con retinoblastoma.

Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins

This study shows a strong association between cell attachment to substratum and activation of beta 1-integrin-signaling with resistance to the camptothecin derivative topotecan (TPT) in breast cancer cells. We propose a mechanistic-driven approach to sensitize the cells to camptothecins. ZR-75-1 anchorage-dependent breast cancer cell line, its derivative 9D3S suspension cells (9D3S-S), and 9D3S cells attached to fibronectin-coated plates (9D3S-A) were treated with TPT (1 microM) or CPT-11 (40 microM) for 48 h. Programmed cell death (PCD), as shown by poly(ADP-ribose) polymerase (PARP), pro-caspase-3 and pro-caspase-9 cleavage, was observed in 9D3S-S cells but not in ZR-75-1 or 9D3S-A cells. Because p125 focal adhesion kinase (FAK) is a transducer in the beta 1-integrin signaling pathway, it is essential to cell adhesion and it is overexpressed in metastatic breast cancer, we hypothesized that attenuation of FAK might enhance the sensitivity of breast cancer cells to camptothecins. Moreover, inhibition of FAK gene expression by a phosphorothioated antisense oligodeoxynucleotide targeting the portion of the gene encoding amino acids 262-268, increased the sensitivity of ZR-75-1, MDA-MB-231 and MCF7 breast cancer cells to treatment with TPT or CPT-11.

Recent advances in cancer therapy

The treatment of cancer has developed substantially from its conception in the first years of the 20th century. Since the introduction of alkylating agents during second World War, the oncology specialty has markedly grown. In the recent years, new drugs have been approved for the treatment of cancer. Such examples include the taxanes (Docetaxel and Paclitaxel), Vinorelbine, Irinotecan, Topotecan, Gemcitabine and Gliadel. We will discuss these new chemotherapuetic agents, their pharmacology, indications, toxicity and appropriate dosing. There is no doubt that further clinical research is needed to determine the optimal use of these agents