Anemia and fatigue are frequent in lung cancer patients. Anemia is due to cancer and platinum-based chemotherapy. Anemia leads to a wide range of symptoms and affects health-related quality of life. Anemia also worsens outcome of therapy and prognosis. Efficient treatment exist: blood transfusion and recombinant erythropoietin. Early treatment of anemia is recommended as soon as diagnosis is made. But few patients receive optimal treatment. Its cost and unsolved question regarding therapeutic strategies may explain this phenomenon. This debate should not preclude correct treatment prescription. Clinical trials have to be preformed to clarify unsolved questions. As EPO administration can affect survival, this point should be of particular interest in future trials.

Chemotherapy generates numerous adverse effects, but digital ischemia is usually associated with a paraneoplastic mechanism. In addition to thrombotic microangiopathy or hepatic or pulmonary venoocclusive disease gemcitabine appears to induce this type of complication. This study presents two cases of digital ischemia, which are very likely attributable to gemcitabine. The first case involved a 56-year-old female patient with lymph node metastatic squamous cell carcinoma, for which no primitive tumor could be identified. This carcinoma had been treated at a second stage with gemcitabine at a cumulative dose of 14 390 mg. Search for etiology revealed toxic vascularitis. Response was favourable after interruption of gemcitabine and prescription of a suitable medical treatment. The second case was a 74-year-old male patient with an infiltrating bladder urothelium carcinoma with lymph node metastasis. He had been treated by surgery and chemotherapy (gemcitabine and carboplatine). Gemcitabine-induced arterial thrombosis was diagnosed. Nine other cases of digital ischemia were identified in the literature. This rare adverse effect is probably underestimated. The other reported vascular side-effects are thrombotic microangiopathy, with an estimated occurrence of 1 per 6,000 patients and two cases of veno-occlusive disease. The pathogenic mechanisms have still not been fully elucidated. Precautions before use are necessary, especially in case of associated micro or macroangiopathy.

Prolonged use of aspirin and\or non-steroidal anti-inflammatory drugs induces a partial regression of either sporadic adenomas or adenomas in adenomatous polyposis coli (APC), but also their emergence and colonic cancer development in sporadic adenomas. Specific inhibitors of cyclooxygenase of type 2 (Cox2) induce less upper and lower digestive tract adverse events that non-specific anti-inflammatory drugs. This better tolerance might allow a long-lasting use in patients with APC. At time, we don't know if such treatments are able to prevent the development of cancer in the rectum or duodenum of these patients. In this paper we will discuss the scientific proofs and potential interest of Cox2 inhibitors in the treatment of PAF.

Many others cancer agents can lead to cardiovascular toxicity apart from anthracyclines, 5-fluorouracil, trastuzumab and ionizing radiations. Paclitaxel, high-dose cyclophosphamide and ifosfamide, mitomycin and irinotecan cardiotoxicity is unusual but for certain. Hormonal therapy is extensively used in breast and prostate cancers. Thromboembolic and cardiovascular events are increased by estrogens, synthetic progestatives and tamoxifene. Because of major toxicities related to intravenous interleukin-2, subcutaneous interleukin-2 regimens have been developed, allowing an improvement of cardiovascular tolerability. Interferon is less frequently associated with cardiotoxicity. Before treatment initiation, risk factors favouring cardiac toxicity should be evaluated. These risk factors can be related to the cancer agent, to the patient or to the tumour. Uncommon toxic events in general population can be more frequent in high risk patients. Therapeutic option can be influenced by these uncommon toxic events in high risk patients.

Trastuzumab combined to chemotherapy had demonstrated significant improvement of time to progression and survival in metastatic breast cancer patient overexpressing HER-2. Cardiac toxicity was an unexpected side effect. The incidence of cardiac dysfunction was dependent on prior or current anthracycline exposure. The mechanism of action involved for this cardiac toxicity is unclear. We discuss in this article the incidence, the physiopathology, the risk factors, the predictive factors and the patient management and on cardiotoxicity of trastuzumab.

5-fluorouracil (5FU) is a largely employed antimetabolite, responsible for several well-known toxicities like hand-foot syndrome, diarrhoea, mucositis or leucopenia. Cardiotoxicity of 5-FU is known but uncommon and usually not life-threatening. The incidence has varied from 1.5 and 18%. The physiopathology is controversial, although more recent data suggest a myocardial toxicity. Clinical presentation include chest-pain, cardiac arrythmia, myocardial infarction or global cardiac failure. Electrocardiographic features are usually aspecific, with ischemic signs. The main treatment is to stop the 5-FU infusion and to introduce symptomatic cardiologic treatment. Although the prognosis is good, the mortality ranges between 2.2 and 13% in case of symptomatic cardiotoxicity. Secondary prophylaxis remains controversial.

For more than twenty years, tamoxifen represents the gold standard treatment in adjuvant setting for breast cancer patients. However, the tamoxifen activity remains complex, with its agonist effects, sometimes a poor tolerance and a certain number of patients become refractory to treatment. The aromatase inhibitors, such as progestatifs, were developed to challenge tamoxifen efficacy, along with improved tolerability. The third generation of aromatase inhibitors seems to provide significant gains in efficacy over tamoxifen for postmenopausal patients with hormone receptor positive breast cancer and they have already been approved in patients with metastatic disease. We review, in this article, the rationale for using IA in patients with breast cancer and, across the different clinical trials results already published, their current major role they are playing in adjuvant setting for menopausal hormonal receptor-positive breast cancer patient. One of the main issues using the third generation of IA is their long-term side effects, especially bone turnover and lipid metabolism.

PPARg (peroxisome proliferator-activated receptor gamma) is a nuclear receptor that regulates the transcription of numerous genes involved in the differentiation, proliferation and apoptosis of various cell types. It was initially discovered in adipocytes as a differentiation agent, then was characterized in vascular endothelium and recently in choroidal and retinal endothelial cells. Agonists that bind to PPARgamma and stimulate its transcriptional activity are endogenous lipids such as lysophosphatidic acid and 15-d-PGJ2 as well as the synthetic pharmacological compounds, thiazolidinediones, used for treating type 2 diabetes. These ligands prevent choroidal and retinal neovascularization in several experimental animal models, notably through the inhibition of vascular endothelial growth factor (VEGF) receptor expression. Because of the high affinity and the low molecular weight of agonists, suitable for good bioavailability, PPARgamma could potentially be a novel pharmacological target of angiostatic agents, particularly useful to treat age-related macular degeneration and diabetic retinopathy.

Liver metastases of colorectal cancer are rarely rapidly resectable. The efficacy of new chemotherapy regimen, in particular the combination of 5FU and oxaliplatin make further surgical resection possible in the case of an objective response in some patients. Three patients with metastatic colorectal cancer received oxaliplatin-based chemotherapy; only minimal and transient neurosensory toxicity occurred. After a partial response to treatment, surgical resection of metastases was performed. Patients reported major exacerbation of oxaliplatin-induced neurosensory toxicity following surgery (between day 7 and day 15). One patient experienced sensory loss of the extremities with functional impairment (grade 3 on Levi's scale). The symptoms persisted for 812 months after surgery in the three patients. Only seven similar cases have been reported. Toxicity could be associated with the concentration of oxaliplatin in the red blood cells: oxaliplatin binds irreversibly to erythrocytes. This exacerbation could be the consequence of peroperative hemolysis with a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. We did not find any relationship with anesthesic or per-operative medications. Studies are necessary to define the precise mechanism and the frequency of this reaction.

Adrenocortical carcinoma (AC) is a rare tumor of poor prognosis. Its treatment by o,p'DDD remains a reference after initial surgery. Two galenic forms were recently available in France: Lysodren and Mitotane AP-HP. As Lysodren got a European registration in april 2004, Mitotane is no more produced. O,p'DDD is an adrenolytic and cytotoxic agent. It also reduces the hormonal secretion in AC. Its blood level must reach a therapeutic window (14-20 mg/l) to be effective and to limit toxicity. It is given orally three times a day (3 grams a day for Lysodren and 6-12 grams a day for Mitotane. Its posology is adapted according to serum levels of o,p'DDD and tolerance. Side effects are essentially gastrointestinal (GI), neurologic and hepatic. Five patients (four with AC and one with a metastatic Leydig cell tumor of the testis) were treated by Lysodren. Three patients had early Lysodren discontinuation due to toxicity (skin rash, weight loss, GI toxicity). Studies of combination with other treatments as chemotherapy and targeted drugs are warranted. Surgery is an important part of metastatic disease treatment.

During the treatments of carcinomas of the cervix, anemia is relatively frequent and its origin is complex combining often hemorrhage, iron deprivation, inflammatory reactions and infection. The frequency of the primary anemia (hemoglobin level<12 g/dl) is correlated with clinical stage and varies from one publication to another, mainly from 25% for stage I, to 33% for stage II and can approach 40% for stage III. Anemia is correlated with patient survival and it appears to be one of the most powerful prognostic factor after clinical stage and tumor size. Anemia is a bad prognostic factor related to stage and tumor size but it has not been proven to be an independent factor. Anemia increases hypoxia of cervix carcinomas, which is an independent prognostic factor for patients N0. Moreover, we know that the oxygenation of these tumors is correlated with hemoglobin levels. The normalization of Hb levels by transfusion could certainly modify the prognosis of patients anemic before treatment, or of those becoming anemic during radiotherapy treatment. For smokers, anemia is certainly more important that we can appreciate from the Hb levels only, by the presence of carboxyhemoglobin. Concomitant chemotherapies with cisplatin compounds are actually standards and they can largely increase the risk of inducing anemia, therefore more than 50% of patients will experiment it during their different treatments. Transfusion is recommended by the SOR (Standards Options and Recommendations of the Fédération nationale des centres de lutte contre le cancer) under 10 g/dl. The use of erythropoietin is a therapeutic option for Hb levels between 10 and 12 g/dl and strongly recommended after a Hb normalization by blood transfusion. For 70% of patients who respond to erythropoietin, a better control of the Hb level is obtained. The impact of this anemia on quality of life and treatments compliance justifies the use of erythropoietin, especially in cancers for which treatments induce a deep fatigue and a very bad tolerance, which could be a limiting factor.

EGFR is overexpressed and is associated with a poor prognosis in head and neck cancer. Among the biological and cellular effects resulting from EGFR targeting in head and neck cancer there is the capacity to restore apoptotic capacities. Other experimental results put into evidence that DNA-repair activity was reduced by the application of EGFR targeting agents. This context was in favor of a research oriented towards combination between anti-EGFR drugs and cytotoxic agents, particularly irradiation. Supra-additive cytotoxic effects have been observed at the experimental level when combining anti-EGFR drugs with irradiation in head and neck cancer. These experimental data were recently confirmed at the clinical level in locally advanced head and neck cancer.

Despite its teratogenic effects, thalidomide has been reintroduced in human anticancer treatment for its anti-angiogenic activity, especially observed in patients with multiple myeloma. Here, we report the synthesis of new analogues designed to increase the thalidomide anti-tumour properties. The anti-angiogenic activity of the compounds was tested on EA.hy 926 endothelial cell lines. In this model, that is easier to manipulate than HUVEC cells, thalidomide is active in a similar dose range as reported on HUVEC cells and one of our compounds is more efficient.

Ras proteins belong to the monomeric GTPases familly. They control cell growth, differentiation, proliferation, and survival. Ras mutations are frequently found in human cancers and play a fundamental role in tumorigenesis. Ras requires localization to the plasma membrane to exert its oncogenic effects. This subcelllular localization is dependent of protein farnesylation which is a post translational modification catalysed by the farnesyl transferase enzyme. Farnesyl transferase Inhibitors (FTI) were then designed ten to twelve years ago to inhibit ras processing and consequently the growth of ras mutated tumor. Preclinical data show that FTIs inhibit cell proliferation and survival in vitro and in vivo of a wide range of cancer cell lines, many of which contain wild type ras suggesting that mutated Ras is not the only target of the FTIs effects. Four FTIs went then through clinical trials and three of then are still developed in the clinic. Phase I et II clinical trials confirmed a relevant antitumor activity and a low toxicity. Phase III clinical trials are currently undergoing for both solid and hematologic tumors. The expected results should allow to define the position of FTIs as anticancer drugs, particularly in combination with conventional chemotherapy, hormone therapy, radiotherapy or any other new targeted compound.

Because of the unavailability of effective therapies to block or reverse the progression of androgen-independent prostate cancer, it seems obvious to target growth signaling pathways for which frequently recurring mutations have been identified. Acquired mutations of the PTEN gene have been reported in several tumor types, including up to 30% - 60% of prostate cancer tumors. This results in constitutive activation of the PI3K/Akt pathway which then represents a major target to prevent dysfunctions in cell growth, survival and motility. Our experience and, therefore, our own tools allow us to design new inhibitors of growth factor receptor tyrosine kinase, PDK-1 and farnesyltransferase activities. These original compounds could selectively switch off one or several steps of the multifunctional pathway and constitute lead compounds in the design of new classes of potent drugs.

Podophyllotoxin, a natural lignan, is a good inhibitor of tubulin polymerization with antitumoral properties but it is too toxic for therapeutic use. In order to obtain less toxic drugs, several heterolignans have been prepared. We presented the synthesis and preliminary pharmacological properties of 4-aza-2,3-didehydropodophyllotoxins (dihydropyrrole [3,4-b]quinolin-1-ones), a new azalignan series. A straightforward synthesis was described according to a multicomponent reaction in a one-pot procedure. Starting from an aniline, an aromatic aldehyde, and a cyclic B-diketone, many substituted analogues could be prepared. Our lead, the 4-aza-2,3-didehydropodophyllotoxin, is extremely cytotoxic on various tumor cell lines, active in vivo on murine tumors. Like podophyllotoxin, this drug inhibits microtubule assembly without any effect on depolymerization.

Three glucuronyl prodrugs of paclitaxel have been synthesized in order to be activated by the B-glucuronidase present within the necrotic areas of tumors. As three compartments containing prodrugs, they include a specifier, a self immolative spacer and the drug. In vitro testing clearly indicates that the two former prodrugs are stable and are more or less detoxified. As expected, in the presence of E. coli B-glucuronidase, the glycosidic linkage is hydrolyzed with a rate depending on the nature of the spacer but, once this hydrolysis has occurred, the self immolative spacer is soon eliminated leading to the liberation of the paclitaxel.