Laboratorio per Identificare Nuovi Farmaci Antimetastasi

The research programs concerning the drugs active against metastases of solid tumours originate from the laboratory studies on the first models of metastatic tumours. As it is well known, in order to study a drug, the availability of an effective model of the disease against which that drug is to be used is required.

Starting on the early studies of the intra-tibial implant of Ehrlich's ascitic cancer used to stimulate a bone-affecting metastasis, today we have several models of expermental tumours that exibit an extraordinary resemblance to human ones. These models have been greatly useful both to the comprehension of the biology of the metastasis spread, and to the understanding of the reasons for the scant response of human tumour metastases to the conventional pharmacological treatment (chemotherapy). The research presently uses these models, and since the mid-seventies on many new and innovative drugs have been proposed, capable of interfering with the metastasis building process.

Actually, if on one hand it is becoming apparent that the solid tumour metastases are often derived from a cellular subset of the primary tumour capable of surviving to the hostile extra-tumour environment of the host and of moving freely within the body until some of them get implanted in a target-organ, thus generating a secondary tumour (metastasis), on the other hand parallel researches were discovering that such a metastasis was less sensitive to chemotherapy than the average cells of the primary tumour, that it was less visible to the immune system and that its growth kynetics was different from that of the primary tumour cells. It became therefore evident that the same drugs that were effective against the primary tumour were not necessarily active also against tumour derived metastases.

That accounted for the unsatisfactory activity shown by many chemotherapics against metastatic diseases: they were drugs developed upon cytotoxicity studies carried on using models that mostly simulated the behaviour of primary tumours. The target of such research programs was to find chemicals capable of interfering with cell division, reckoning with the different growth speed between healthy and neoplastic tissue, obviously in favour of the latter. Drugs derived from this approach did not show any capability of discriminating between tumour and healthy tissue, and therefore had - all of them - an activity heavily conditioned by their toxicity to the host, in some cases pronounced enough to drastically limit their use.

In the last 10 years a very accurate multicentric research work has brought to discovering the anti-metastasis properties of a ruthenium-based complex, identified as NAMI-A.

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Connectival capsule (C) of primary tumour. A: control; B: treated NAMI-A

Although ruthenium belongs to the same group of platinum, this complex shows some quite unexpected properties and, unlike cisplatin, one of the most powerful anti-tumoral drugs introduced in human therapy in the sixties, is selectively active against tumour metastases at doses nearly harmless for the healthy tissues, at least when compared to the most common clinically employed anti-cancer drugs.

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Intra-tumoral blood vessels of primary tumour. A: control; B: treated NAMI-A

The anti-metastatic effect of NAMI-A is the combination of effects on the primary tumour, consisting of
the increase of the connective capsule and of the extra-cellular matrix, in particular around the tumour blood vessels, and of the reduction of the mass of pulmonary metastases.

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Pulmonary metastases of mammary cancer MCa. A: control; B: treated NAMI-A

The discovery of cisplatin stimulated the research on transition metals complexes, aiming at:

Quite naturally the work carried on has been homogeneous as far as the cisplatin complexes were concerned, several thousands of which have been studied, whereas the studies on metals other than platinum have been absolutely fragmentary.

Since the discovery of the remarkable anti-tumour properties of NAMI-A, a swarm of research projects can be predicted having ruthenium as a reference metal. Such research projects have the advantage of homogeneising the fragmentary studies presently available and allow to recruit new laboratories that find an interest in the study of these new complexes.

LINFA therefore intends to anticipate the events by offering a sound and already operating support to those who want to undertake this challenge.

LINFA employs basic research methods, typical of pharmacological investigation. In particular, molecules whose study is proposed to LINFA, after a discussion between the Executive Commmission and the proposers, are first examined according to metastases investigation models using cell cultures. Next, the most promising molecules undergo an in vivo investigation using solid metastasising tumours in rodents. In detail the investigation is about:

a) the direct effect on the proliferation capability of tumour cells as a function of the complex uptake, measured by means of suitable markers and with the aid of flow cytometry and atomic absorption spectrometry;

b) the anti-tumour effects mediated by immune system cells and by components of the extra-cellular matrix by means of histology, immune-histochemical and enzymology techniques; and

c) the compared effects on the metastasis capability and the in vivo systemic toxicity.