Hydroxyurea is an antitumour agent used most commonly to treat myeloproliferative disorders. We present a clinical observation illustrating different cutaneous side effects susceptible to occur during a long-term treatment by hydroxyurea : leg ulceration, oral ulcer and spinocellular carcinoma. This clinical observation is completed by a review of the literature published on the cutaneous side effects of hydroxyurea treatment.

Paclitaxel is an anti-neoplastic agent commonly used in the treatment of primary bronchial carcinoma and tumours of the breast and ovary. Its toxicity, haematological and peripheral neuropathy, are well known. On the other hand central nervous system toxicity is rare.

Endothelin-1 (ET-1) and angiotensin II (AngII), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (ETA-R and ETB-R for ET-1, AT1R and AT2R for AngII) that all belong to the superfamily of G-protein coupled receptors. There is increasing evidence that ETA-R, ETB-R and AT1R are expressed in a variety of cancer cells and tissues, and may play a role on tumor growth, angiogenesis and invasion in vivo. This review summarizes the similarities and differences between the ET-1 and AngII systems with regard to their reported effects on various aspects of cancer. In addition to being expressed on vascular endothelium, ET-1 and AngII receptors participate in tumor angiogenesis through the production of the angiogenic factor VEGF. Furthermore, recent clinical studies indicate that a selective ETA-R antagonist has beneficial effects in prostate cancer, suggesting that a similar approach using ETB-R and AT1R blockers might be envisioned. Experimental data presented here suggest that a combined therapy targeting both ET-1 and AngII systems may prove valuable for future treatments of highly angiogenic tumors.

Telomeres are composed of single-strand DNA rich in guanine which can adopt particular structures such as T-loop or G-quadruples, a four-strand DAN structure formed by guanine repeats. Telomeric single-strand DNA is the substrate of telomerase, an enzyme necessary for telomeric replication which is suppressed in most cancer cells and which participates in tumor genesis. The formation of a telomeric G-quadruplex blocks telomerase activity and offers an original strategy for new anti-cancer agents. Using an original approach combining rational screening and synthesis, several series of compounds have been identified which specifically bind to the telomeric quadruplex. These derivatives, called "G-quadruplex DNA ligands", are able to block telomeric replication in cancer cells and provoke replicative senescence and/or apoptosis after a few cell cycles. Our team is working on characterizing the cellular and molecular mechanisms of action of these ligands. Using mutant cell models resistant to these ligands or expressing a protein cuff covering the telomere in tumor lines, we have demonstrated that the telomere is the principal intracellular target of action of these compounds and the implicit existence of the G-quadruplex structure. In collaboration with academic and industrial partners, optimization of these ligands to develop pharmacologically active products should enable in vivo validation of a new therapeutic concept.

The risk of venous thromboembolism (VTE) is increased in association with malignancy, and has a potential to produce significant morbidity and mortality. Treatment of such patients with anticoagulants is associated with both benefit and a high rate of complications. In the early phase, the treatment is usually achieved with low molecular weight heparin (LMWH), which has a number of advantages over unfractionated heparin (UFH): once or twice daily administration, no necessary laboratory monitoring, lesser risk of bleeding and no drugs interactions. Nevertheless, the UFH is the anticoagulant of choice when a rapid anticoagulant effect or stop of anticoagulant effect is required, in the treatment of massive pulmonary embolism or severe renal insufficiency. Prolonged anticoagulation with LMWH (over 3 or 6 months) appears to be beneficial on survival for such patients. The subject of anticoagulation in patients with primary or secondary brain tumours is controversial. The long-term anticoagulation mainly use LMWH or vitamin K antagonist. The last ones are more difficult to use because of an unpredictable response with higher rate of recurrence and bleeding. The optimal duration of treatment is not known but the patients should be treated for at least 6 months, even at least 12 months after a second episode of venous thromboembolism. On the primary prevention in high-risk surgical oncology, the LMWH are at least as effective and safer as UFH when the optimal dose was administered. For the medical patients, the use of prophylactic anticoagulant treatment is less clear except the patients who are bedridden for prolonged periods of time. For the secondary prevention, the LMWH seems to be more effective over vitamin K antagonists. For these patients, the anticoagulant therapy is recommended indefinitely or until cancer is resolved.

5FU is one of the most frequently used antioncogenic and cytostatic drug in digestive oncology. It may cause severe adverse events, such as encephalopathy, possibly based on hyperammoniemia, and may lead to coma. We report here the case of a coma with a favorable outcome following 5FU chemotherapy. As any other etiologic findings came to light, hyperammoniemia was discussed as a credible cause.

Gestational trophoblastic tumors are authentic malignant tumors of the conception. They are mostly chemosensitive. For young women, the place of the surgery seems now restricted and more and more codified. Hysterectomy keeps a certain interest for women who do not wish to preserve their fertility. Hysterectomy limits then the complications of chemotherapy. It optimizes the chances of recovery without recurrence. If chemotherapy must nevertheless be carried out, hysterectomy decreases the necessary number of cures to obtain complete remission of the disease. Surgery is also indispensable to chemoresistant tumors. It allows exeresis of localized residual sites or isolated metastases. Other indications for surgery include uncontrollable vaginal or intra-abdominal bleedings and placental site trophoblastic tumors.

Dacarbazine (DTIC) is the first-line chemotherapy for metastatic malignant melanoma without cerebral metastasis. Its clinical and hematological safety is usually good. Hypersensitivity in hepatic failure patients is the most serious side effect described.

Oxaliplatin is a reference drug in the treatment of digestive-tract tumors, especially colorectal cancer. Its toxicity profile is dominated by a peripheral sensitive neuropathy, with neuromuscular manifestations. This neurotoxicity has 2 components: an acute toxicity characterized by a rapid onset of cold-induced distal dysesthesia and/or paresthesia, muscular contractions, numbness, stiffness, usually transient but able to evolve into a chronic, persistent sensory peripheral neuropathy that eventually causes functional impairment. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. This neurotoxicity is frequent, 80%of the patients and becomes chronic in 15 to 20%of the patients, sometimes irreversible. The mechanism of this neurotoxicity has been elucidated: an increased neuronal excitability is due to the action of oxaliplatin on voltage-gated sodium channels through chelation of calcium by the oxaliplatin metabolite. The prevention of this neurotoxicity is a major goal, taking in account the wide indications of this drug. Different approaches have been or are evaluated, based on pathogenic or practical concepts: 1) modifications of the administration schedule; 2) substances acting upon sodium channels : calcium-magnesium, carbamazepine, gabapentine, venlafaxin; 3) detoxifying agents and antioxydants: glutathion, amifostine, alphalipoic acid, tocopherol ; 4) substances used in other kinds of neuropathy: glutamine, alphalipoic acid; 5) neurotrophic factors: NGF, LIF; 6) oxaliplatin analogs, with a DACH platin, without oxalate. Calcium-magnesium infusion seem to be an efficient and safe approach. Further studies are necessary for a better understanding and prevention of this neurotoxicity, potentially severe.

Programmed cell death or apoptosis is a crucial process for normal embryonic development and homeostasis. Apoptosis is known to be coupled to multiple signalling pathways. Identification of critical points in the regulation of apoptosis is of major interest both for the understanding of control of cell fate and for the discovery of new pharmacological targets, particularly in oncology. Indeed, defects in the execution of apoptosis are known to participate in tumour initiation and progression as well as in chemoresistance. The Bcl-2 family members constitute essential intracellular players in the apoptotic machinery. Those proteins are either pro or anti-apoptotic, they interact with each other to regulate apoptosis. Inhibiting the heterodimerisation between pro- and anti-apoptotic members is sufficient to promote apoptosis in mammalian cells. Small molecules, antagonists or peptidomimetics inhibiting this heterodimerisation, represent a therapeutic prototype targeting the apoptotic cascade. They induce cell death by activating directly the mitochondrial apoptotic pathway. Considerable evidence indicate that such Bcl-2 antagonists could be useful drugs to induce apoptosis preferentially in neoplastic cells.

Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy.

Therapy for renal cell carcinoma has made considerable progress in the past few years. The aims of this review are to update the pathological classification of this tumor and discuss predictive factors for tumor response and survival in the case of metastasis as well as the place of immunotherapy with interleukine-2 and/or interferon alpha . Furthermore, we will review new therapeutic options and current results on allogeneic stem cell transplantation with non-myeloablative conditioning and HLA genoidentical donors. Finally, we will present targeted therapy (antiangiogenic drugs and tyrosine kinase inhibitors) with the mechanisms of action, efficacy and appropriate use in the treatment of metastatic renal cell carcinoma.

This year, the innovations were numerous in sarcomas. Important progress were accomplished in the search for predictive factors which make it possible to propose to the patient a personalized treatment with the therapeutic ones reduced in the event of good prognosis or on the contrary aggressive steps in the event of bad prognosis. These prognostic factors can be genetic or clinical. Progress were also accomplished in the clinical field with the research of the most adapted therapeutic strategies and of advanced in various drugs of chemotherapy in particular the ET-743. Lastly, research is active and of many ways are tested into preclinic with a detailed attention on the way of the angiogenesis.

Molecular targeted agents have enlarged the armamentarium of anti-cancer therapies. Along with the success of some anti-growth factor receptors, signal transduction inhibitors represent a promising anti-cancer strategy. The PI3K-AKT-mTOR pathway is a key pathway frequently altered in cancer cells. This manuscript provides an overview of the PI3K-AKT-mTOR pathway and its targeting in human malignancies. A focus is delivered for mTOR inhibitors.