New strategies with greater antitumorous efficacy

One of the biggest problems in the current treatment of cancer is that the agents that are efficacious in the destruction of tumorous cells are, at the same time, extremely toxic for the rest of the healthy cells and tissues of the patient.

To address the problem the University of the Basque Country (UPV/EHU) is seeking more specific treatments and studying the differences between tumorous cells and healthy ones.

A research team from the Faculty of Medicine and Odontology is working on identifying pharmacological agents that increase the therapeutic benefit of combinations of chemo-, immune and radiotherapy agents in the treatment of cancer ailments.

The aim of the research team was to identify compounds that act on the metabolic pathways and processes that take place differently depending whether a diseased tissue of a patient or healthy tissue is involved; in this way selective action can be undertaken, increasing the sensitivity of treatments for diseased tissues without damaging healthy cells or tissues at the same time.

With this general goal the researchers tested various biomodulators on a number of different tumorous modules such as melanoma, sarcoma and cancer of the colon. On the one hand, they studied agents that modulated levels of glutathione (GSH) – key element in the biological processes of cells, both healthy and tumorous. Tumorous cells with high GSH levels have a greater growth and metastatic capacity and a lower sensitivity to antitumorous agents. On the other hand, one of the features of tumorous cells is that they lose their normal level of differentiation and, instead of exercising a determined function, they start to proliferate and generate a greater quantity of tumorous cells. This is why the researchers have also used agents that induce differentiation, such as are retinoids.

More selective therapies

Both groups of modulators have been associated with classic agents used in antitumorous therapies and have seen the benefits arising therefrom. They have shown that the GSH level modulating agent - oxothiazolidine-carboxylate (OTZ) increases the antitumorous effect in antitumorous cells and, at the same time, protects healthy tissue. In this way the therapeutic benefit can be increased. Nevertheless, when another GSH-level modulating agent is combined with antitumorous agents, for example, buthionine-sulphoxamide (BSO), the researchers observed that the effect of the standard drug was increased but that an increase in damage to healthy tissue also took place.

Also, with the aim of returning the cells to a more differentiated state, closer to healthy cell behaviour, this research team is investigating the use of retinoids in combination with standard agents. The response of tumorous cells to retinoids depends on the degree of differentiation of these cells. In general, highly differentiated tumorous cells are more sensitive to retinoids than moderately differentiated ones are. These latter, in response to retinoids, may trigger defence mechanisms that augment GSH levels and, in this way, increase metastatic capacity.

This is an interesting point, given that to date this different capacity that can have different cell lines within the same tumorous type has not been described. What the UPV-EHU researchers have done is to link both lines of modulation -GSH modulation and that of the differentiation inductors. They have found a link between the two – the induction of differentiation with retinoids also modulates the GSH levels of tumorous cells.

Researchers are analysing the model for the concentration and administering of the agents used, given that, in the biological modulation, both elements are found to be fundamental for the success of the treatment. The concentration is not a matter of the more the better, but the optimum response involves a specific concentration, because too little or too much may produce opposite or undesired effects.

Following in vitro and in vivo trials by researchers at the laboratories of the UPV/EHU, one of the goals of the research team is to transfer the information obtained to more easily managed systems for research and for clinical trials.