Callerio Foundation

Linfa

LINFA - Within the Callerio Foundation, a worldwide reference point for researchers who investigate anti-metastatic ruthenium-based drugs and their pharmacological properties.

LINFA has the main task of promoting the research on pharmacological treatment of solid tumor metastases based on ruthenium complexes, and originates from the experience cumulated by researching the properties of a new drug within this family.

Callerio Foundation and anticancer metal-drug development


STATE OF THE ART

Platinum-based drugs (in particular cisplatin and oxaliplatin) have marked cancer chemotherapy for the last 40 years. Beside their indisputable activity, these drugs share with almost any other chemotherapy drug a significant host toxicity and the possibility to induce resistance in cancer cells. These two aspects have been and still are the main targets for the development of new platinum-based drugs capable of replacing cisplatin and its analogues with new compounds more active and capable of circumventing tumour resistance and/or exibiting a lower toxicity.

The current approaches, in the preclinical development of new platinum-based drugs, pursue theese targets:

i)
circumvent resistance;
ii)
to include activity on refractary tumours;
iii)
to improve pharmacokinetics, particularly in orally administrable drugs.
These goals are pursued with compounds directed to G-G rich DNA regions (in telomers for example), or with compounds suitable for activation by small pH differences (usually lower in solid tumour masses) or by intracellular components such as the GSH-GSSG system (anyhow invariably directed to guanines of cellular DNA).

The evaluation of the status of the art in EU, in which the COST D20 (2000-2006) project is specifically oriented on "Metal Compounds in the Treatment of Cancer and Viral Diseases" and, more generally, in the world, as results from the recent Symposium on Platinum Compounds in Cancer Chemotherapy, held at NY, USA, on October 2003, gives us a picture with few differences: mainly, it appears that in EU there is a slightly more interest

i)
to study also compounds with metals different from platinum;
ii)
to include more "imaginative" structures and
iii)
to evaluate some pharmacological besides the usual chemotherapy mechanism.

WHAT IS A POSSIBLE FUTURE?

Although, there is an apparently general refractoriness of the "platinum club" to study compounds active on targets different from DNA bases, it is time to capitalize the enormous knowledge on metal compounds in the context of the significant advancements on the biology of tumour cells.

Germane to this subject, for example, is the possibility to study "metals":

1)
targeted to cytoskeleton molecules, including adhesion cell membrane and extracellular matrix components;
2)
controlling the pro-angiogenic activities of cancer cells;
3)
active on signalling pathways regulating molecules;
4)
or on caspase activation in caspase-deficient cells;
5)
or even on metastatic cells or on single tumour cell phenotypes.

WHAT IS A OUR STRATEGY?

LINFA, with the activation of the project MADE (MetAl compounDs in the postgenomic Era), forces the idea that these compounds may change the actual view of cancer treatment: from "cytotoxic, irreversibly active", chemotherapics to "pharmacologically active" drugs.
The goal is to obtain compounds

i)
active at the physiological regulation of cell behaviour with loss of the "malignant" phenotype,
ii)
endowed with selective recognition of cancer cells (reduced or null side-effects), that will allow
iii)
the individual tumour type treatment.
This strategy can be pursued:
a)
giving chemists a number of "biological labs" with expertise in cell biology and cancer growth;
b)
supporting the use of "metals" that do not necessarily show strong DNA-interaction;
c)
selecting "biological tests" predictive of activity on malignant cells;
d)
including contacts with "Pharma Co" to allow rising of patents;
e)
studying "surrogate" endpoints to ascertain drug efficacy.

WHAT LINFA OFFERS

LINFA and MADE choose Ruthenium and offer full collaboration to those who will share this challenge.

LINFA and MADE will stimulate joint research programs on Ruthenium-based compounds targeted to cell cycle, signalling transduction and adhesion molecules. The research programs will extend the knowledge on the pharmacological effects of "sulfoxide-rutheniums" to other compounds and will lead training courses for young scientists in conjunction with major institutions in EU.