Cancer chemotherapy: a critical analysis of its 60 years of history.

Chemotherapy has already proven widely effective in the treatment of cancer, occupying a prominent place in the current therapeutic arsenal. However, in recent years, there has been a plateau in the evolution of the clinical results obtained with this modality treatment. In some cases, the limitations of chemotherapy observed during the early days still apply. These facts forced us to do a thorough analysis of what happened in the past 60years. We have observed that each major advance obtained in this field was based on empirical clinical observations. We thus believe that the current results of old or new agents can only be improved by understanding the natural history of each specific cancer subtype at the clinical level and by overcoming the physiological barriers involved in chemotherapy failure. This strategy will surely allow us to enlarge the list of curable cancers by chemotherapy.

The cytotoxic activity of Aplidin in chronic lymphocytic leukemia (CLL) is mediated by a direct effect on leukemic cells and an indirect effect on monocyte-derived cells.

Aplidin is a novel cyclic depsipeptide, currently in Phase II/III clinical trials for solid and hematologic malignancies. The aim of this study was to evaluate the effect of Aplidin in chronic lymphocytic leukemia (CLL), the most common leukemia in the adult. Although there have been considerable advances in the treatment of CLL over the last decade, drug resistance and immunosuppression limit the use of current therapy and warrant the development of novel agents. Here we report that Aplidin induced a dose- and time-dependent cytotoxicity on peripheral blood mononuclear cells (PBMC) from CLL patients. Interestingly, Aplidin effect was markedly higher on monocytes compared to T lymphocytes, NK cells or the malignant B-cell clone. Hence, we next evaluated Aplidin activity on nurse-like cells (NLC) which represent a cell subset differentiated from monocytes that favors leukemic cell progression through pro-survival signals. NLC were highly sensitive to Aplidin and, more importantly, their death indirectly decreased neoplasic clone viability. The mechanisms of Aplidin-induced cell death in monocytic cells involved activation of caspase-3 and subsequent PARP fragmentation, indicative of death via apoptosis. Aplidin also showed synergistic activity when combined with fludarabine or cyclophosphamide. Taken together, our results show that Aplidin affects the viability of leukemic cells in two different ways: inducing a direct effect on the malignant B-CLL clone; and indirectly, by modifying the microenvironment that allows tumor growth.

In vitro susceptibility of CD4+ and CD8+ T cell subsets to fludarabine.

Administration of the adenosine analogue fludarabine (FLU) in vivo induces a profound and prolonged T lymphopenia which mainly affects CD4(+) cells. To better understand the mechanistic basis underlying this preferential depletion, we analyzed the in vitro susceptibility of T cell subsets to FLU-induced apoptosis. Contrasting with observations in vivo, our results showed that treatment of peripheral blood mononuclear cells with FLU induced a higher level of apoptosis in CD8(+) than in CD4(+) T lymphocytes. This increased sensitivity of CD8(+) T cells to FLU was observed in samples from both, healthy donors and B cell chronic lymphocytic leukemia patients, and resulted in higher CD4:CD8 ratios in FLU-treated than in untreated cultures (P<0.01). Expression of factors involved in FLU transport and metabolism was then evaluated by quantitative real time-PCR in normal T cell subsets. It was found that mRNA levels of human equilibrative nucleoside transporter-1 nucleoside transporter were higher whereas deoxycytidine kinase and IMP/GMP selective 5'-nucleotidase mRNA levels were lower in CD4(+) cells. However the dCK/cN-II ratio was 2-fold greater in CD8(+) than in CD4(+) T lymphocytes, which could account for the higher apoptosis levels observed in the CD8(+) subset. These results favor the view that decreased CD4:CD8 ratios in FLU-treated patients should be attributed to differences in cell recovery and/or homing between T cell subsets.

P-glycoprotein expression by cancer cells affects cell cytotoxicity and cell-cycle perturbations induced by six chemotherapeutic drugs.

BACKGROUND: P-glycoprotein (P-gp)-mediated chemoresistance plays an important role in drug resistance. METHODS: We investigated if P-gp expression by cancer cells affects cell cytotoxicity and cell-cycle perturbations induced by six commonly used chemotherapeutic agents (doxorubicin, daunorubicin, mitoxantrone, vinblastine, paclitaxel, and colchicine). For this purpose, we used KB cell lines as a model and flow cytometric cell viability and drug-induced cell-cycle perturbation-based methods. We continuously cultured KB cell lines, in the presence of various anticancer agents and measured the cell-cycle kinetics and percentage of cell viability by flow cytometry at different time intervals. RESULTS: The highly resistant cell line KB V-1 was significantly less susceptible to drug cytotoxicity than the sensitive cell line KB 3-1. KB V-1 cells cultured with different chemotherapy agents continued cell-cycle progression without any significant perturbation of cell compartment distribution. Addition of verapamil, by inhibiting P-gp, reversed resistance thereby increasing drug cytotoxicity and allowing the appearance of drug induced cell-cycle perturbations. CONCLUSIONS: We conclude that P-gp interferes with cell cytotoxicity and cell-cycle perturbations induced by anticancer agents. Flow cytometry can be used to conveniently detect P-gp-mediated chemoresistance by cancer cells as it allows the analysis of cell cytotoxicity and cell-cycle modifications after exposure to specific chemotherapeutic and reversal agents.

Un modelo regulador para el cáncer: la evidencia y las estrategias a seguir / Regulator model for cancer: evidence and strategies to follow

¿Qué es el cáncer? ¿Cómo podemos prevenirlo? ¿Cómo podemos minimizar su morbilidad y mortalidad?. Nuestro acercamiento a estas preguntas depende de como nosotros conceptualizamos el cáncer. Por más de cien años, nosotros pensamos que las células tumorales están irreversiblemente fuera de control, matando inevitablemente al huésped a menos de que fueran totalmente erradicadas. Desde 1970, los Estados Unidos de Norteamérica declararon la guerra contra el cáncer. Como una real guerra, la posibilidad de batir el cáncer dependerá del poder de nuestro armamentario químico. La premisa central de este modelo asesino es: es necesario luchar nás para matar más, siendo la completa desaparición del tumor la única posibilidad de lograr la cura. Regímenes con intensificación de dosis son usados para matar la última célula. Pero hoy en día, nosotros sabemos que aunque tenemos poderosas armas, nosotros perderemos la guerra en la mayoría de nuestros pacientes. Es tiempo de parar la guerra y cambiar el paradigma del cáncer. Nosotros necesitamos comprender que el cáncer es un proceso dinámico, la consecuencia clínica de los sistemas regulatorios normales parcialmente fuera de control. Este proceso está caracterizado por un desequilibrio regulatorio y este desequilibrio es potencialmente reversible. Esto significa que la cura funcional no requiere una remisión completa. Además, las estrategias asesinas pueden ser contraproducentes. Nuevas tendencias en el diagnóstico y tratamiento y sus resultados dependerán de este nuevo modelo regulatorio. El modelo regulatorio cambia la manera aunque nosotros investigamos, prevenimos y tratamos el cáncer. Le atrae la próxima gran aventura en oncología. (AU)

Un modelo regulador para el cáncer: la evidencia y las estrategias a seguir / Regulator model for cancer: evidence and strategies to follow

¿Qué es el cáncer? ¿Cómo podemos prevenirlo? ¿Cómo podemos minimizar su morbilidad y mortalidad?. Nuestro acercamiento a estas preguntas depende de como nosotros conceptualizamos el cáncer. Por más de cien años, nosotros pensamos que las células tumorales están irreversiblemente fuera de control, matando inevitablemente al huésped a menos de que fueran totalmente erradicadas. Desde 1970, los Estados Unidos de Norteamérica declararon la guerra contra el cáncer. Como una real guerra, la posibilidad de batir el cáncer dependerá del poder de nuestro armamentario químico. La premisa central de este modelo asesino es: es necesario luchar nás para matar más, siendo la completa desaparición del tumor la única posibilidad de lograr la cura. Regímenes con intensificación de dosis son usados para matar la última célula. Pero hoy en día, nosotros sabemos que aunque tenemos poderosas armas, nosotros perderemos la guerra en la mayoría de nuestros pacientes. Es tiempo de parar la guerra y cambiar el paradigma del cáncer. Nosotros necesitamos comprender que el cáncer es un proceso dinámico, la consecuencia clínica de los sistemas regulatorios normales parcialmente fuera de control. Este proceso está caracterizado por un desequilibrio regulatorio y este desequilibrio es potencialmente reversible. Esto significa que la cura funcional no requiere una remisión completa. Además, las estrategias asesinas pueden ser contraproducentes. Nuevas tendencias en el diagnóstico y tratamiento y sus resultados dependerán de este nuevo modelo regulatorio. El modelo regulatorio cambia la manera aunque nosotros investigamos, prevenimos y tratamos el cáncer. Le atrae la próxima gran aventura en oncología.