New approaches to cancer therapy

S. Garattini

Istituto di Ricerche Farmacologiche "Mario Negri", Via Eritrea 62, 20157 Milano, Italy

*E-mail: mapelli@marionegri.it

In the last decade there has been a decrease, for the first time in Europe, in the age-standardized mortality for all cancers [1], from 147 to 136 per 100 000 inhabitants per year. The reasons are many, and include preventive interventions, early diagnosis, changes in lifestyle (mostly giving up tobacco smoking) and better treatments, at least for some tumors [2]. However, with notable exceptions, pharmacological treatments are responsible for only a small fraction of cancer cures, although they are credited with an increase of survival in some cases [2]. Even the latest drugs on the market do not achieve the desired improvement considering the expectations generated by the advances in fundamental knowledge of cancer cell proliferation and dissemination [3].

To be of clinical interest a drug must provide measurable advantages to patients or to national health services. In other words, it should be more effective than placebo or any other effective treatment; if there is no advantage in terms of efficacy, it should at least be safer, more tolerable, easier to use or cheaper than its comparators. Outcome measures should be objective, ultimately establishing the rate of survival and/or the quality of life.

A recent review [4] pointed out that the drugs licensed up to the end of the year 2000 are not particularly innovative. In most cases the dossiers presented to the European Agency for Medicines Evaluation were hampered by small numbers of patients, short treatment duration, lack of adequate comparisons with other drugs and lack of hard therapeutic end points.

In addition, new drugs are often not substitutes for old ones, but are candidates for second- and third-line treatment of rare cancers; they are evaluated in small phase II trials that assess alleged equivalence or non-inferiority (rather than superiority) to standard treatments. The cost of these new preparations is, in addition, almost always several times—sometimes an order of magnitude—higher than existing drugs. This difference is difficult to justify, considering that the newer drugs are at best largely equivalent to standard treatments in efficacy and safety [4].

Some new approaches, such as monoclonal antibodies, still need further evaluation [5]. Rituximab has been considered very active in B-cell follicular lymphomas [6], but unfortunately resistance arises [7]. Trastuzumab, another monoclonal antibody for the second-line treatment of advanced metastatic breast cancer expressing the epidermal growth factor receptor 2 protein (her-2), does not show the expected selectivity, because it induces cardiotoxicity, particularly in combination with anthracyclines [8]. Temozolomide, an analog of procarbazine, has been suggested for the treatment of glioblastoma and anaplastic astrocytoma, but serious doubts about its real efficacy have been raised [9]. Capecitabine is just a pro-drug of 5-fluorouracil [10]. Docetaxel is an analog of paclitaxel, with no documented advantages.

Significant advances since 2000 may be imatinib mesylate, an inhibitor of three tyrosine kinases, ableson, platelet-derived growth factor receptor and KIT [11, 12], which induces remissions in chronic leukemia [13] and gastrointestinal stromal tumors [14]. However, relapses due to resistance have been described for this drug as well [15].

In the treatment of non-small-cell lung cancer expectations of another tyrosine kinase (epidermal growth factor receptor tyrosine kinase) inhibitor, gefitinib [16], have not been met.

Although the overall outlook is still discouraging, for the first time in the history of cancer pharmacology an array of new approaches is now available, whereas up to a few years ago the only mechanism available was cytotoxicity or inhibition of cell proliferation. Among these new approaches, some are already being assessed in clinical trials.

Chemoprevention is gaining importance in relation to the role of nutrition in cancer prevention [1719]. A long list of compounds with different chemical structures isolated from various kinds of vegetables counteract the effect of carcinogenic agents by different mechanisms, including activation of cytochrome P-450 [20] and transport proteins such as PgP [19, 21]. Cycloxygenase inhibitors, especially COX-2, reduce colon polyposis [22]. Retinoids [2327] and tamoxifen [28] are other approaches under clinical investigation.

Inhibition of angiogenesis is a popular new chapter of anticancer therapy, based on the fact that newly formed cancer vessels are fragile but essential to supply cancer cells with oxygen and nutrients. The discovery of the vascular endothelial growth factors and their receptors [29] led to the development of an array of endogenous and synthetic antiangiogenic products. Many of these are now under clinical investigation but, independently of the results, this approach will still take a long time to develop. An alternative to reduction of the vascular supply is vascular targeting, which aims at destroying already formed vessels. Examples are the coaguloligands [30] and other agents that reduce blood supply, such as combrestatin-A [31].

Efforts to counteract resistance are concentrated on developing inhibitors of multidrug resistance [3234] and O6-alkylguanine-DNA alkyltransferase [35].

Apoptosis is a biochemical pattern of suicidal behavior of cancerous and normal cells that has attracted considerable attention as the mechanisms involved have become clearer. Drugs that increase apoptosis or antagonize factors responsible for antiapoptotic activity, such as survivin [36], are of interest for combination therapy. Retinoids are credited with apoptotic activity [37] in addition to their cytodifferentiating activity [38]. Efforts are being made to elucidate the different mechanisms in order to obtain compounds with selectivity. Fresh knowledge of the mechanisms involved in the dissemination of cancer cells and formation of metastases [39] offers opportunities for the discovery of new drugs. A variety of other approaches are under study, including inhibition of specific targets such as proteasomes [40], matrix metalloproteinases [41] and farnesylprotein transferases [42]. Other promising potential drugs selectively localize to mitochondria [43] or bind the DNA minor groove [44]. Natural marine products include the promising ectenaiscidin-743 [45], at present under clinical investigation.

Vaccines in cancer refer to the induction of a systemic immune response ‘after’ rather than ‘before’ the antigen insult. Therefore these vaccines aim at inducing a specific T cell rather than humoral response. Methods, mechanisms, results and limitations of anticancer vaccines are reported in the review in this issue.

Gene therapy is, for the time being, a theoretical approach, although several trials are in progress. Early enthusiasm has been attenuated by difficulties when moving from animals to man.

Although there are now a considerable number of valid theories on how to control cancer, there are some intrinsic problems in achieving a cure, particularly for solid tumors, that cannot be ignored. First, tumors are not a single disease, but a variety of diseases which, according to previous results, have selective sensitivity to specific anticancer agents. For instance, cisplatin is certainly more active on testicular than on lung cancer. Genotyping has shown that what looks like a single disease when investigated by the common technique of histological staining may actually be different cancers, with different prognoses, requiring different treatments [46].

Secondly, not only may tumors of the same group be different, but even within the same tumor in the same patient, not all the cells are similar. Not all the cells show the same degree of malignancy: some are more prone to migrate and induce metastasis in other parts of the body, sometimes in a selective manner; some cells have a native resistance to certain drugs while others are sensitive to low concentrations of anticancer agents. Mutations occur in some cells but not in others, resulting in different genotypes [47], and proteomic research will undoubtedly find differences in the protein profile.

Recent findings confirm the substantial differences between single cancer cells that may present thousands of random mutations. When exposed to an anticancer drug, neoplastic cells with pre-existing mutations that make them resistant are able to proliferate and eventually repopulate the tumor [47].

Thirdly, in addition to presenting thousands of mutations, cancer cells are plastic and can easily adapt themselves to environmental changes. Various mechanisms of resistance have recently been elucidated, confirming Ehrlich’s assumption that ‘resistance follows chemotherapy as a faithful shadow’. Cells can develop enzymes to inactivate drugs; they can develop mechanisms to extrude anticancer agents from the cells via specialized proteins such as PgP [4851]; they can repair the DNA damage [35]; they can create channels instead of blood vessels [52]; and they can develop various biochemical mechanisms to counteract the action of anticancer agents [15].

Fourthly, the entry of drugs into the tumor depends on the vascular system; the blood supply to tumors is usually quite rich on the surface but much poorer inside, where there is usually a considerable amount of necrotic material [53]. This explains why experimental [54] and human tumors [55] show a range of drug concentrations, depending on where the tumor is located and where on it the drug concentrations are measured. This gradient in drug concentrations is another important reason for resistance. The problem of cancer vascularization will become even more important for large molecules such as antibodies, antisense nucleotides, vaccines, gene therapy or, even more, stem cells.

Fifthly, although cancer cells differ in several respects from normal cells, it has been difficult to exploit this difference so far. Therefore anticancer drugs, whatever their innermost mechanisms of action, are likely to exert toxic effects on normal cells as well. This is illustrated by the already-mentioned cardiotoxicity of trastuzumab, a drug that binds specifically to her-2 receptors. This situation tends to reduce the possibility of raising the dose of anticancer agents, because their toxicity is a limiting factor. The use of drug combinations is certainly very important, although so far, with limited exceptions, it has not proved to be the final solution.

These intrinsic difficulties in the pharmacology of cancer suggest that new approaches will also have to meet the challenge of these obstacles. To discuss these problems, this journal will publish a series of reviews on therapeutic interventions beginning with the article by G. Parmiani on the prospects for cancer vaccines [56]. It is hoped that new therapeutic approaches, alone or in combination, will give the answers that patients have been expecting for a long time.

S. Garattini

Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy (E-mail: mapelli@marionegri.it)

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