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Cytotoxic chemotherapy is important for treatment of patients with hormone-insensitive advanced breast cancer. A variety of new cytotoxic agents are promising alone or in combination. The originality, the clinical activity and side effects, as well as the current development status of these agents are reviewed. These agents include the new antimicrotubules (analogues of taxanes and vinorelbine; epothilone derivatives), oral formulations of 5-fluorouracil and other antimetabolites (tomudex, alimta, gemcitabine), liposomal anthracyclines, platinum analogues, topoisomerase I inhibitors and other compounds such as ET-743. Finally, new molecular-targeted therapies of potential interest in the treatment of metastatic breast cancer are reviewed. The growing availability of such biological therapies given alone and mainly in combination with hormonal and chemotherapeutic agents may improve in the near future the outcome of patients with metastatic breast cancer.

The number of elderly women diagnosed with breast cancer by 2025, will increase by 72%. These elderly women do not yet participate in most screening programmes. One notes more favourable biological characteristics of the tumour, including more expression of steroid receptors (oestrogen receptor, progesterone receptor), low proliferative rate, good differentiation, normal p53 and low expression of epidermal growth factor. Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy and chemotherapy. There is a paucity of data to substantiate that such an approach is better than a more radical one. The efficacy of chemotherapy and guidelines for its use vary by tumour stage and patient age. Drugs like modified anthracyclines, vinorelbine, the taxanes and capecitabine may be changing the paradigm of combination therapy superiority.

Malignant melanoma is a notoriously aggressive disease that can affect relatively young individuals and whose incidence is rising at an alarming rate. Unlike many cancers, metastatic melanoma is poorly responsive to current therapies and mutations affecting p53, the retinoblastoma gene product or Ras which occur frequently in many other cancer types, appear to be rare or at least relatively late events in the progression of the disease. Recent advances in our understanding of the disease at the molecular level have indicated that in addition to the loss of cell cycle checkpoints which may be common to all cancers, malignant melanoma shares many characteristics in common with developmental precursors to melanocytes, the mature pigment producing cells of the skin and hair follicles which are responsible for skin and hair colour. This review therefore focuses on the signalling pathways that play a crucial role in the development of the melanocyte lineage which are subject to deregulation in malignant melanoma namely signalling by receptor tyrosine kinases, the Wnt signalling pathway, as well as loss of the p16INK4a cyclin-dependent kinase inhibitor. Intriguingly all three pathways impact on the expression or function of the microphthalmia-associated transcription factor which plays an essential role in melanocyte development.

The chloroethylating nitrosoureas (lomustine, fotemustine, cystemustine (BCNU) and methylating agents temozolomide (TMZ), dacarbazine (DTIC), procarbazine) have documented activity in metastatic malignant melanoma with single agent response rates of 15-25%. Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.

Major prognostic factors for melanoma include thickness of the primary lesion, ulceration and presence or absence of regional lymph node metastases. These parameters form the basis for the American Joint Committee on Cancer staging system and the determination of the appropriateness of post-surgical adjuvant therapy. Among the numerous agents tested for the adjuvant therapy of high-risk melanoma, interferon-alpha 2b (IFN-alpha2b) administered at maximally tolerated doses is the only one to demonstrate an improvement in relapse-free and overall survival for these patients. This high-dose IFN-alpha2b regimen comprising an intensive intravenous induction phase followed by a more prolonged subcutaneously administered phase has now been tested in three, large, randomised trials done through the United States Cooperative Groups, and has shown consistent benefit in preventing relapse and improving survival for patients with thick primary melanomas and those with regional lymph node metastases. The relative importance of the induction component of this treatment regimen is being addressed in an ongoing intergroup trial for intermediate-risk melanoma. Data from completed and ongoing studies using high-dose IFN-alpha for the adjuvant therapy of melanoma are presented.

The field of melanoma immunobiology has made tremendous strides in the past decade, resulting in the molecular identification of a vast array of tumour-expressed antigens that contain determinants that are recognised by patient T cells or immunoglobulins. The integration of these antigens, their derivative peptides or improved analogues in vaccine trials allows for the augmentation of melanoma-specific CD4+ and CD8+ T cells in situ that may prove clinically efficacious in the adjuvant or therapeutic setting. Indeed, melanoma peptide-based immunotherapies targeting the activation of anti-tumour CD8+ cytotoxic T lymphocytes have proven successful (i.e. yielding objective clinical responses), particularly when combined with T cell growth factors or potent antigen-presenting cells, such as dendritic cells. Vaccine approaches implementing poly-epitope and/or melanoma peptides recognised by CD4+ T cells are anticipated to yield still better clinical outcomes due to the in vivo promotion and maintenance of a diversified, poly-specific effector T cell repertoire directed against resident tumours.

Incidence and mortality of human malignant melanoma has risen rapidly over recent decades. Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing although immunological treatment has been more successful for melanoma than for most other tumours. With the availability of recombinant cytokines, immunotherapy for melanoma has entered a new era and a growing body of evidence suggests the efficacy of these approaches in pre-clinical models. Cytokine gene transfer to tumour cells has been demonstrated to induce tumour rejection in different murine melanoma models suggesting that vaccination with tumour cells genetically engineered to produce cytokines is an attractive strategy to enhance anti-tumour immune responses in patients with melanoma. Taken together, these data may hold significant promise for the development of effective ex vivo and in vivo systemic and gene therapy modalities to counter the highly metastatic nature of human melanoma.

Immune responses against human melanoma are common and are believed to influence the natural history of the disease. In particular, CD4 T cell infiltrates are associated with regression of primary melanoma and with responses to treatment with interferon-alpha2 (IFN-alpha2). Our studies have shown that CD4 T cells appear to kill melanoma by means of a member of the tumour necrosis factor (TNF) family expressed on their surface and called TNF related apoptosis inducing ligand (TRAIL). Moreover, sensitivity to TRAIL also predicts responsiveness of melanoma to CD4 T cells. TRAIL is not expressed on resting lymphocytes but is expressed at high levels after exposure to IFN-alpha2 and on activated T cells. Lymphocytes from melanoma patients in early stages of the disease show high levels of expression after exposure to IFN-alpha2 and IFN-gamma but expression was less on lymphocytes from stage IV patients. This may be due to factors from melanoma cells in that supernatants from some melanoma cultures suppressed IFN-alpha2 upregulation of TRAIL. Sensitivity of melanoma cells to TRAIL can be increased by inhibition of the activation of NF-kappaB and anti-apoptotic events downstream of NF-kappaB. These results suggest that TRAIL may be an important mediator of responses against melanoma induced by immunotherapy or by treatment with IFN-alpha2 and interleukin-2. Studies on surgical biopsies of melanoma however show that fresh isolates appear less sensitive to TRAIL-induced apoptosis and effective therapy may involve combinations with other agents.

Gene-environment interaction can be defined as a different effect of an environmental exposure in people with different genotypes, or a different effect of a genotype in people with different histories of environmental exposure. Interaction applies when one stratum (high risk) responds differently to an exposure (sun) than another stratum (low risk). Genetic predisposition would appear to be a very important modifier of risk. This paper discusses the concept of gene-environment interaction applied to cutaneous melanoma through discussion of highly penetrant genes and their interaction with sun exposure, through discussion of low penetrant genes and their interaction with sun exposure, and by suggesting a new model for investigation of gene-environment interaction in melanoma. It is stressed that this area of investigation is extremely early in its development.

Oligodendroglioma (ODG) constitute a specific type of gliomas, with a better prognosis than astrocytic tumours of similar grade. No clear criteria exist to differentiate astrocytoma from ODG, leading to a significant inter-observer variation in the diagnosis of ODG. ODG are genetically characterised by chromosomal lesions in the 1p36 and the 19q13.3 regions. ODG tumours without these lesions but with TP53 lesions or glioblastoma multiforme-like genetic lesions (loss of chromosome 10 and amplification of 7p) probably constitute a different entity with an oligodendroglial phenotype. Recent clinical trials have shown that ODG are sensitive to chemotherapy with 60-65% of patients responding, with a median response duration of 1-1.5 years. This holds for both low and high-grade ODG; the response rate in mixed oligoastrocytomas may be slightly less but is still better than that of pure astrocytic tumours. There is a strong correlation between a favourable response to chemotherapy and the presence of 1p36 and 19q13.3 lesions, suggesting this may be used to select patients for treatment. The presence of 1p lesions is also related to a longer progression free survival after radiation therapy, implicating that the assessment of the presence of 1p lesions is an important prognostic tool for ODG. The chemosensitivity of ODG is not limited to the PCV schedule. Ongoing trials are investigating whether adjuvant chemotherapy after surgery and radiation therapy provides better survival and quality of life in newly-diagnosed anaplastic ODG. However, even patients with a good response to chemotherapy will ultimately relapse. This calls for improvement of the chemotherapy schedules and for improvement of second line chemotherapy. In the near future molecular analysis may become an important tool to identify tumours that are likely to respond to chemotherapy.