Laboratorio per Identificare Nuovi Farmaci Antimetastasi

LINFA originates from the experience cumulated in the course of studies on the most important pharmacological properties of a new ruthenium-based antimetastasis drug.

LINFA poses itself as a reference point for research on the antimetastasis properties of new complexes being identified within scientific institutions for basic research on the subject.

LINFA has the main goal of promoting studies on the pharmacological treatment by means of ruthenium-based drugs of metastases released by solid tumours.

In the initial stages of working in LINFA all the compounds proposed were tested, without any discussion on the nature of the chemical characteristics of the compounds themselves. However, the goal of getting selective compounds for treating solid tumour metastases would have needed the definition of specific targets.
Selectivity is certainly not achieved through the capacity of some metal-based complexes to bind bases (i.e. guanine) or to bend DNA on the minor or major groove. On the contrary, selectivity might result from the research that biologists, geneticists, molecular and structural chemists, and pharmacologists have done to highlight the relevance of the fine mechanisms that regulate cancer growth and metastasis formation, suggesting new selective targets for cancer chemotherapy. LINFA wants to adhere to these new knowledges and wants to address the chemistry of metal-based compounds to explore these new targets.
Therefore, no more testing of “unspecific” compounds but the choice of targeted compounds aimed at inhibiting metastasis growth through the modulation of the metastatic physiological signals that keep metastases alive.

Up today, preliminary testing in LINFA of preclinical potential of new compounds based on heavy metals have been suggested and done on the basis of the results obtained with sulfoxide-ruthenium complexes. Provided that LINFA decided to select compounds by excluding those with in vitro  cytotoxicity for tumour cells, emphasis has then been put on:

• lack of in vitro  cytotoxicity;
• arrest of cell cycle at G₂-M phase;
• inhibition of matrigel invasion;
• inhibition of MMPs activity and/or release.
  

On a pure speculative basis, there is no need for changing this sequence of test. Exhaustive data from literature have stressed the role of proteinases on angiogenesis, invasion and metastases. Thus, these test have good possibility to highlight compounds with good activity against metastasis formation and growth.
However, compounds to be tested cannot come out of empirical synthesis nor they should be the result of the classical design of DNA interacting agents. Conversely, we propose to study new compounds designed to be capable of interacting with mediators of the Signaling Transduction Pathways (STP). There is now considerable evidence of the involvement of altered STP in cancer growth and in cancer malignancy. These alterations depend on the modulation of genes, often fully silenced after differentiation, which correspond to autocrine and paracrine modulations of cell mechanisms atypical of differentiated cells.

For future preclinical screening in LINFA, emphasis will then be put on:

• in vitro cytotoxicity;
  [in comparison experiments with healthy and tumour cell lines]
• modification of cell distribution on cell cycle phases;
  [including analysis of cell cycle regulating complexes]
• inhibition of matrigel invasion;
  [and also of cell motility]
• inhibition of MMPs activity and/or release.
  [combined with extracellular matrix degradation]
  
  WHAT
  
  LINFA will examine compounds based on metals of platinum group and of other transition series. The aim is to get compounds designed to specifically interact with targets of the STPs involved in cancer growth and metastasis.
  LINFA expects that this approach will favour the appearance of new generation metal-based compounds capable of selective interactions with the active sites of specific kinases and proteins involved in the maintenance and/or activation of malignancy.
  
  WHY
  
  Because of their nature, metal-based compounds have shown an enormous potential of interaction with biological components.
  Their design as agonists or antagonists of the active site of macromolecules involved in the crucial steps of atypical cell growth and division might then give rise to results unexpected with the organic compounds synthesised as yet. The relative small dimension, the high number of biologically important ligands that can be linked and the potential of the electronic interactions provided by the combination of oxidation state of the metal centre and of the ligands themselves, allow metal-based compounds to exhibit interesting pharmacological properties, among which, for example, mobility across biological relevant barriers, high selectivity and intrinsic activity.