Metal compounds in the treatment of cancer and viral diseases

Objective

A.General background
A1:Why a COST Action on this topic

Although metallic elements (e.g. gold) or simple inorganic materials (e.g. minerals containing arsenic or mercury), have been in medical use for as long as several thousand years, a rational basis for their use is only beginning to emerge. Recognition of the role of inorganic Chemistry in life processes has greatly been supported by the development of a discipline now termed " bio-inorganic Chemistry" in the sixties of this century. It has been a fortunate coincidence that during this time one of the most potent antitumour agents, the metal containing drug cis-dichlorodiammineplatinum(II), Cisplatin, has been discovered. These developments took place not in Europe, but in Australia and the US, respectively.

The launch of the COST D1 action "Co-ordination Chemistry in the Context of Biological and Environmental Studies" in 1991 and its start a year later may be considered a belated sign of a European awareness of important developments at the crossroad of biology, inorganic Chemistry, medicine and physics. For the first time, research groups interested in this exciting interdisciplinary field found a forum for exchange of ideas and collaboration. The subsequent COST D8 action "The Chemistry of Metals in Medicine", launched in 1995 and started in 1996, originated from the COST D1 action and was aimed at dealing with all medicinal aspects of inorganic Chemistry. This action has been extremely successful and has now gained a momentum that calls for further concentration on individual topics. There are presently more than 30 laboratories organised in five working groups (0004, 0007, 0009, 0012, 0017) within the COST D8 programme which are doing research on the various aspects of the role of metal ions or metal complexes in antitumour or antiviral chemotherapy. Clearly, the number of laboratories has reached a critical mass to justify formation of a new COST action with a specific focus on "Metal Compounds in the Treatment of Cancer and Viral Diseases (MCCV)".

A2:Status of Research in the Field

The discovery of the antitumour activity of Cisplatin, first reported in 1969 in Nature, and its promising activity against testicular cancer seen in the early seventies, has made platinum (Pt) containing drugs a major focus of research. It has been estimated that of ca. 1000 Pt compounds synthesised and evaluated in test systems, 10 - 20 are good enough to make it to the clinics, a success rate matched by no other class of (organic) antitumour compounds. Today it is undisputed that platinum drugs represent a unique class of antitumour agents. There is hardly any clinical regimen of combination chemotherapy today that does not contain Cisplatin or one of its analogues. Clinical applications include now, apart from testicular cancer, in particular ovarian cancer, lung cancer (non-small-cell and small-cell forms), cancers of the head and neck, urothelial cancer and various cancers of the upper gastrointestinal tract and the cervix as well as osteosarcoma and others. There are presently important developments in the clinical application of new Pt containing drugs ongoing. This comprise the introduction of a new Pt drug in the treatment of colon cancer, the appearance of orally active Pt drugs, the discovery of novel di- and trinuclear Pt compounds, as well as new Pt compounds displaying a trans-geometry of the leaving groups. Several features of these new drugs, e.g. positive charge of di- and trinuclear species or trans-geometry are totally unexpected in that they do not meet criteria of activity established in the early days of Cisplatin. Moreover, many of the novel Pt drugs are cross resistant to Cisplatin. Due to the large potential of these new drugs, there is substantial interest from pharmaceutical companies in these developments.

At an early stage it became evident that DNA is a, most likely the crucial target of Pt containing antitumour drugs. This observation has led to an enormous boost of metal-nucleic acid Chemistry. One has to keep in mind that the first fully established (by single crystal X-ray diffraction) metal binding pattern to a nucleobase, a constituent of a nucleic acid, dates back to 1970 only. Meanwhile an estimated 30 different binding patterns of metal ions are unambiguously established, by far the most examples being for Pt species. Much of the knowledge gained from Cisplatin-DNA related work has proven to be useful for related areas such as heavy-metal toxicity or mutagenicity, the role of metal ions in RNA splicing (ribozyme catalysis), the role of metal ions in gene regulation, and the degradation of nucleic acids by metal entities.

The mode of action of Cisplatin is not fully understood as yet, except for the first steps, which include passive transport into the cell, activation through chloride hydrolysis, and DNA binding. The major DNA cross-link, that between two N7 sites of adjacent guanine nucleobases ("intrastrand G,G cross-link") as well as several others, have been studied in great detail. The original simple concept of a steric blockage of DNA functions (replication, transcription) due to the Pt adduct is no longer considered the ultimate reason for antitumour activity, however. Rather it is now believed that the initial DNA adducts trigger, through protein factors recognising the damage, a complicated cascade of reaction pathways which involve multiple players (HMG proteins, repair enzymes, possibly p53, others) and results in cell death (apoptosis).

Recognition of the significance of Pt-DNA interactions in the process of antitumour activity has spurred the view that interference of Pt drugs (or metal drugs in general) with viral nucleic acids could be of importance also in the treatment of viral diseases, at least if these are life-threatening. Moreover, over the years there has been a growing interest in all aspects of this Chemistry, especially also in the interference of essential metal ions with antiviral nucleotide analogues. Recent recognition of the role of metal ions (Zinc, Zn(II)) in the folding process of a protein crucial of the AIDS virus (HIV nucleocapsid protein) has provided a new target for HIV therapy. It requires, however, a comprehensive understanding of the role of metal ions in this process.

A3:Relationship with other European Programmes

Several conference series, both on a world wide international scale, with visible European participation, and on a European level have been set up since the early 80's to encourage scientific exchange in the field of bioinorganic Chemistry and specifically on antitumour metal compounds. These are:
(i)Biannual "International Conferences on Bioinorganic Chemistry (ICBIC)", held in Florence (1983), Algarve (1985), Leiden (1987), Cambridge, USA (1989), Oxford (1991), San Diego (1993), L_beck (1995), Yokohama (1997), Minneapolis (1999), with average participation of now 800 - 900 scientists;
(ii)Biannual "European Bioinorganic Chemistry Conferences (EUROBIC)", held in Newcastle (1992), Florence (1994), Noordwijkerhout (1996), Sevilla (1998) and to be held in Toulouse (2000), with an average participation of 350 - 400 scientists;
(iii)"International Symposium on Applied Bioinorganic Chemistry (ISABC)", with the 5th conference organised in April 1999 for the first time in Europe (in Corfu, Greece), following conferences in China (2), Australia, and South Africa;
(iv)"European Research Conferences (EURESCO)", held in different places, among others in Albufeira, Portugal (1994), San Miniato, Italy (1995), Tomar, Portugal (1997 and 1999);
(v)Various other national or bi- and trilateral conferences on this theme.

There have been various attempts on the national level to strengthen bioinorganic Chemistry in Europe, e.g. through the establishment of the Royal Society of Chemistry (UK) Discussion Group "Inorganic Biochemistry" (350 members) or a very successful "Schwerpunktsprogramm Bioanorganische Chemie" of the Deutsche Forschungsgemeinschaft (DFG).

As far as journals dealing with bioinorganic Chemistry aspects are concerned, the extremely successful launch of the "Journal of Biological Inorganic Chemistry (JBIC)" in 1996 needs to be mentioned. The journal, founded and presently headed by a European Chief Editor, with 2 (out of 5) additional editors from Europe, had a fantastic start, reaching within 3 years of appearance an astonishingly high impact factor (IF) of 3.750 (source ISI, 1998). Another journal, on "Metal-Based Drugs", initiated during the time of the HCM programme is doing fine, and another international journal, "Biometals", now in its 12th year, has been founded in Europe and has a strong participation of European Scientists in its Editorial Board.

B.Objectives of the Action and Scientific Content

B1:Main Objective

The main objective of the Action is to further develop the Chemistry of metal containing compounds to be applied in cancer chemotherapy and eventually in antiviral therapy.

Recent promising developments in the field of antitumour metal compounds call for major research efforts in this area. The number of European laboratories interested in the topic is sufficiently large to undertake a combined attempt to tackle long-standing and novel questions and come up with innovative answers. Therefore the main means of the proposed COST action will be to provide a forum for intensive scientific exchanges and collaborative works between individual groups in Europe as well as the promotion of scientific networks to solve targeted problems.

While the scientific programme will depend on the projects submitted, there is a will to encourage research in certain priority areas, which appear to be of particular high interest.

B2:Secondary Objectives

1. Design of novel, "non-classical" metal antitumour drugs, viz. compounds with structural principles different from those based on cis-geometries of Cisplatin and its analogues.

Among these, complexes of platinum with a trans-geometry, complexes with a positive charge (and not neutral, as in the case of Cisplatin), and multinuclear complexes (carrying two or more metal ions) are to be mentioned. By now it is evident that some of these complexes display a striking activity against Cisplatin-resistant tumours.

2.Design of new principles of metal antitumour and metal antiviral drugs, e.g. inclusion of metal entities in "antigene" and "antisense" strategies of gene silencing.

These new strategies are among the most elegant routes of chemotherapy in that they aim at the source of any genetics-related disease, DNA and RNA, respectively, rather than attacking proteins that manifest disease. Metal ions can potentially play an important role in the inactivation of crucial gene sequences (or their RNA transcripts) by acting as a "glue" between the target sequence and the chemotherapeutic oligonucleotide.

3.Design of new cellular targets for metal antitumour agents, e.g. for guanine quartets in telomeres and inhibition of telomerase activity by suitably devised cationic metal entities.

As recently recognised, activation of the enzyme telomerase is the most common single biochemical change in human tumours, and telomerase levels frequently correlate with disease progression. Inactivation of this crucial enzyme can be achieved, among others, by maintaining or stabilising the folded structure of the chromosome ends, the so-called telomeres. They contain guanine quartets, which are naturally stabilised by metal ions and represent excellent targets for metal-related approaches.

4.Study of active cellular uptake of metal antitumour drugs (e.g. transferrin-mediated uptake of Ru drugs).

Among the foremost goals of chemotherapy is selective cell damage. Any active transport process favouring tumour cells over healthy cells is potentially useful to selectively increase the drug concentration inside the malignant cell. There is some indication that the transferrin shuttle can be exploited in getting active metal drugs (and not just Fe, as is normally the case) inside tumour cells.

5.Role of metal compounds in cleavage reactions (hydrolysis; redox Chemistry) of nucleic acids and their potential use as therapeutic agents.

Nature uses metal ions as efficient catalysts for many processes, including the formation and the degradation of nucleic acids. The latter feature can be applied as a chemotherapeutic approach by damaging nucleic acids prior to the formation of undesired proteins. Combined with objective 2 (e.g. conjugates between "antisense" or "antigene" agents and hydrolytically active metal entities), this approach could be highly selective.

6.Study of mechanism of action of antiviral nucleotide analogues in the context of nucleic acid polymerases.

The possibility exists that the metal binding properties of diphosphorylated nucleotide analogues are intrinsically associated with their antiviral activity by irreversibly blocking the active site of the polymerase. Thus the proper spacing of two metal ions at the interface between substrate and the polymerase enzyme in the active site appears to be crucial.

7.Development of novel high through put cytotoxicity testing assays and novel preclinical testing assays.

Combinatorial approaches for the identification of active metal drugs require a modification of presently available technology and need to be developed. Likewise, novel fast screening methods making use, for example, of mechanism-based approaches (as opposed to conventional cell-toxicity tests) need to be established.

C.Organisation Management and Responsibilities

C1:Management

The objectives described under section B2 are a selection of very important sub-topics which are already stimulated in several European member countries and which are very promising for co-ordination at the European level.

C2:Responsibilities

The Management Committee has responsibilities for:
(1)Drawing up the inventory during the first year, organisation of workshops and start of the activity; existing contacts (see section A3) will be used which should greatly facilitate this task;
(2)Co-ordination of the joint activities with other COST Actions; joint meetings are likely to result from this activity;
(3)Explore the possibilities for wider participation and exchange of information with EU-specific programmes, ESF, etc;
(4)Planning the intermediate report, final report and concluding symposium.

The respective participants will also provide reports on the progress of each of the projects in their own countries within the framework of existing programmes.

C3:Evaluation of Progress

The progress of the programme will be monitored by means of brief annual reports from each of the participating scientists. This will describe the results of research obtained through co-ordination. A mile stone report ought to be prepared by the Management Committee after 2 years of joint activities. The report will be presented to the COST Technical Committee for Chemistry for their review and to the COST CSO for information.

A final report will be published to inform non-participating scientists and research workers interested in the results about the scientific achievements of the Action. It is expected that some reviews by participants will describe the progress made and state of the field will be published in International Journals. To conclude the COST Action, a symposium will be held after 5 years. It will be accessible to other scientists.

D.Time-table

The programme will cover five years and consist of four stages:

Stage 1:After the first meeting of the Management Committee a detailed inventory of on-going research and existing plans of the participating groups to begin joint projects will be made. This will result in a discussion document to allow further planning.
Stage 2:It will be evident which projects are closely related and would benefit from joint activities. Researchers (and co-workers) will set-up (and continue) joint collaborative projects and exchange their recent research results. It may be appropriate to explore wider collaboration with other European countries during this stage.
Stage 3:An intermediate progress report will be prepared after two years for review by the COST Technical Committee for Chemistry and by the COST Senior Officials Committee.
Stage 4:This final phase will begin after four years and will involve the evaluation of the results obtained. It will include the organisation of a symposium for all the participants and co-workers. The final report will be submitted to the COST Technical Committee for Chemistry for a scientific assessment and after to the COST Senior Officials Committee.

In summary the total timetable can be represented as follows:
-Start 1st year
-Formation of projects 1st-2nd year
-Workshop of group leaders end of 1st year
-Overview available; start meetings; continue meetings on subtopics 2nd-3rd year
-Start exploration of wider participation after end of 1st year
-Intermediate Progress Report available for Technical Committee and CSO end of 2nd year
-Start evaluation of results after 1st year
-Concluding Symposium 5th year

E.Duration of the Action

The Action will last for five years: 2000-2004.

F.Economic dimension of the Action

It is to be expected that the five working groups presently in the COST D8 action will transfer into the new COST action, following some regrouping and extension by additional laboratories. It is estimated that a total of 40 laboratories will eventually be involved in the action.

Based on experience in the COST D8 programme, it is estimated that the economic dimension of the Action (initial estimate of total costs = personnel + operational + running + Commission costs) will be 100 M EURO.

The total human efforts in the Action "Metal Compounds in the Treatment of Cancer and Viral Diseases" as described in this document, amounts to 800 man-years, being equivalent to 80 M EURO.

1.Personnel costs

Estimated of personnel costs (research and administrations) are 80 M EURO.

2.Operational and running costs

The estimate of the total operational and running costs including costs of instruments and materials is 20 M EURO

3.Co-ordination costs

The costs for co-ordination to be covered by the COST budget are estimated to be 80 000 EURO per year, giving a total of 400 000 EURO for 5 years of the action. (0.4%)

F.DISSEMINATION OF SCIENTIFIC RESULTS

All publications arising from research carried out under COST Action D20 will credit COST support and the Management Committee will encourage and promote all co-authored papers. Results of research carried out by the working groups under COST Action D20 will be submitted to international scientific journals and reviews.

Joint meetings among different working groups in COST Action D20 and with working groups from other COST Actions, particularly with those of COST Actions D8, will be organised in such a way as to best promote interdisciplinary communication.

The Management Committee (MC), in conjunction with the working groups (WG) of the Action, will meet every year with the main aim of presenting results to the MC as a whole and, where possible, the MC will invite potential users and interested parties to this meeting.

The Management Committee (MC) will, during the first year of the Action, also set up a work-plan for interdisciplinary events for the dissemination of results of the Action.

Programme(s)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Topic(s)

13 - Chemistry

Call for proposal

Data not available

Funding Scheme

Data not available

Coordinator

N/A

EU contribution

No data

Address

Germany

Total cost