The acridone alkaloid acronycine, isolated from several Sarcomelicope species (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, subsequent clinical trials only gave poor results, probably due to the moderate potency of this drug. The isolation of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope led to a hypothesis of bioactivation of acronycine by transformation of the 1.2-double bond into the corresponding oxirane in vivo. This hypothesis and the demonstration that acronycine should interact with DNA guided the development of a series of 1.2-dihydroxy-1.2-dihydrobenzo[b]acronycine esters and diesters as novel anticancer drug candidates. In vivo, cis-1.2-diacetoxy-1,2-dihydrobenzo[b]acronycine, selected for further development under the code S 23906-1, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice. The cytotoxic and antitumor activities of these compounds were strongly correlated with their ability to give covalent adducts with purified as well as genomic DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug.

The acridone alkaloid acronycine, isolated from several Sarcomelicopespecies (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, subsequent clinical trials gave limited results, probably due to the moderate potency and poor water solubility of this drug. The isolation of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane in vivo. Consequently, we synthesized a series of cis-1,2-dihydroxy-1,2-dihydroacronycine diesters which exhibited interesting antitumor properties with a broadened spectrum of activity and an increased potency when compared with acronycine. The demonstration that acronycine should interact with DNA prompted us to develop benzo[b]acronycine analogs possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. In vivo, 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine developed under the code S 23906-1, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice. The cytotoxic and antitumor activities of these compounds were strongly correlated with their ability to give covalent adducts with purified as well as genomic DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug.

This retrospective descriptive study documented the frequency of oral mucositis and examined the impact of certain variables in the development of oral mucositis in autologous stem cell transplants. Oral mucositis occurred in 90% of the patients, but 53.57% developed ulcerations. On average, oral mucositis started on day seven, lasted for six days and resolved on day 13 after the initiation of chemotherapy. Sodium bicarbonate mouthwash and mucositis mouthwash were commonly used interventions; 72.92% of the interventions were used as secondary prevention. Oral mucositis was significantly associated with diagnosis (lymphoma), chemotherapy (etoposide and melphalan), and level of prevention (secondary). Diagnosis (lymphoma), chemotherapy (etoposide and melphalan), serum creatinine (peak level), and level of prevention (secondary) were independent predictors of oral mucositis.

Hemolytic uremic syndrome is a rare condition during gemcitabine therapy.

Purpose. - Thalidomide, a major teratogen drug, was rehabilitated mainly in malignant hemopathy. Current knowledge and key points. - Thalidomide-mechanisms of action are well known, multiple, they combine immunomodulatory, antiangiogenic properties, and the modulation of cytokines, particularly tumour necrosis factor-alpha. Multiple trials are ongoing, however, the main indication remain multiple myeloma with a response rate of 30% in relapsed patients. Future prospects and projects. - New structural analogues of the thalidomide which priviligiate some of the thalidomide-specific mechanisms of action, the selected cytokine inhibitory drugs (SelCIDS) and the immunomodulatory drugs (IMiDs) family are under evaluation. The IMiDs, which mechanism is based on stimulation of T lymphopoiesis rather than inhibition of tumour necrosis factor-alpha, are under clinical trials in multiple myeloma with interesting results.

Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However, the narrow therapeutic index of most chemotherapeutic agents and the severe consequences of undertreatment or overdosing have led to research molecular predictive factors of the toxicity and efficacy of cancer treatments. Genetic factors affecting drug metabolism and transport partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of the treatments, that combines the optimal efficacy and the minimal risk of severe side effects. Polymorphisms in genes encoding specific drug-metabolising enzymes can result in individuals in the general population being characterised as low, rapid or even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available that determine or predict the metabolic status of an individual and, thus, enable the evaluation of risk of drug failure or toxicity. Some clinical applications of pharmacogenetics (5-FU, irinotecan, thiopurines) have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips...) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.

Gemcitabine is pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors. Laboratory studies demonstrating that gemcitabine is a potent radiosensitizer led to a variety of trials combining radiation and gemcitabine. In the clinic, phase I-II studies are still trying to determine the optimal dose and schedule which could be use in daily clinical practice. This review summarizes the mechanisms of interaction between radiotherapy and gemcitabine and presents several therapeutic schemes for each tumor location.

Taxanes (paclitaxel and docetaxel) stabilized microtubules against depolymerization, and inhibit their function. Their radiosensitizing properties have been discovered more than 10 years ago; they synchronized tumor cells in G2/M phase, the most radiosensitive portion of the cell cycle. Other radiosensitizing mechanisms have been also discussed, as reoxygenation, promotion of radio-apoptosis and antiangiogenic cooperation. Many phase I and II studies have been performed, essentially in bronchus and head and neck carcinomas. In lung cancer, paclitaxel was delivered weekly at a dose of 60 mg/m2. Many studies combined cisplatin or carboplatin with paclitaxel, demonstrating that this combination is feasible and efficient. Only one phase III trial was reported; after two cycles of chemotherapy for inoperable lung cancers, radiotherapy was delivered, with or without paclitaxel radiosensitization: a benefit in disease-free survival was observed for the combination arm. In head and neck carcinomas, conomitant association of cisplatin, paclitaxel and radiation was feasible and showed promising results. Clinical trials with docetaxel are in progress.

Increased hair loss followed, in some instances by an acute focal or total alopecia, can develop in some cancer patients. The surgical stress or procedure, radiotherapy and some chemotherapy regimens can be responsible for these disturbing events. The alopecia is transient or permanent according to its origin. Diverse diagnostic and prognostic methods are available for assessing alopecias. The trichogram is a rewarding one.

Many substances may be the source of dizziness or transient equilibrium disturbances due to dysfunction of the CNS or to an impairment of visual or proprioceptive informations. Other agents are responsible for drop of arterial pressure by changing position, including antihypertensive drugs, alpha-blocking agents used in urology, antipsychotics, cyclic antidepressants, vasodilators and nitrates, dopaminergic antiparkinson drugs, sedatives, etc. Only drug with true ototoxic properties will be discussed here, namely substances that are able to damage the inner ear (cochlear or vestibular damage) or the VIIIth cranial nerve, causing impairment of equilibrium and/or (most often) hearing. No relevant data report the actual incidence of ototoxic problems, but more than 130 products have been classified as potentially dangerous. Individual susceptibiity seems highly variable, but some predisposing factors have been identified: renal failure, age, combination of ototoxic drugs, familial sensitivity to ototoxic effects or previous neurosensorial deficit. We will first discuss the ototoxic medications that have certainly been extensively studied and among which we find several antibiotics (especially aminoglycosides and macrolides), the loop diuretics, and some antimalarial or chemotherapeutic agents. Environmental toxins and drug of abuse will then be discussed briefly because scientific data are much less significant. Early recognition of subjects who are at risk of developing ototoxicity, use of therapeutic monitoring and close observation of cochleo-vestibular functions in high risk situations (often not easy in critical patients) are the best way to prevent severe complications that have occasionally disastrous consequences on the quality of further life.

Localised seminal vesicle amyloidosis is relatively infrequent and we present 9 additional cases.