Recent developments of rebeccamycin analogues as topoisomerase I inhibitors and antitumor agents

DNA topoisomerases are essential for the survival of prokaryotic and eukaryotic organisms. Topoisomerases inhibitors, due to their capacity to induce DNA breaking, can exhibit interesting antitumor properties. While there are many potent antitumor agents which target topoisomerase II, relatively few families of specific topoisomerase I inhibitors have been identified. The present review describes a new family of topoisomerase I inhibitors, analogues of the bacterial metabolite rebeccamycin. These compounds possess an indolocarbazole chromophore onto which is attached a sugar residue. Important structure-activity relationships studies in this series have helped to understand the role of the carbohydrate moiety which is absolutely necessary for topoisomerase I poisoning, the influence of the stereochemistry (alpha or beta) of its linkage to indole, the influence of the functionalities and substitutions on the sugar moiety and on the aromatic framework have been investigated. In addition to their action on DNA, rebeccamycin analogues may inhibit the SR kinase activity of topoisomerase I and therefore constitute a unique family of topoisomerase I poisons quite different from the well known camptothecins.     

Influence of female sex on asthma

Asthma in women has characteristic features related to hormone secretion. Classically, the prevalence of asthma is higher in boys than in girls. Data in the literature are not all in agreement with this hypothesis and it would appear that for cultural and social reasons, asthma is under-diagnosed in young girls. In the premenstrual context, sex hormones have a clear effect as reported in the literature in 30 to 40% of asthmatic women. Aggravation occurs readily in patients with severe disease. During pregnancy, asthma can influence outcome unfavorably. It is advisable to follow these pregnancies closely and encourage good self-monitoring to minimize risks for the mother and fetus. In the peri- and post-menopausal period, asthma may worsen in women with prior disease. The rate of disease onset during this period is also higher than in other age groups. Hormone replacement therapy can have an unfavorable effect on the incidence of asthma during this period.     

Pyrrolocarbazoles as checkpoint 1 kinase inhibitors

The carbazole framework is found in many natural compounds of biological interest. Indolocarbazoles such as rebeccamycin and staurosporine which are either a topoisomerase I inhibitor (rebeccamycin) or a non selective kinase inhibitor (staurosporine) are bacterial metabolites. In the search for new antitumor agents, DNA damage checkpoint kinases, in particular Checkpoint kinase 1, have recently emerged as attractive targets for cancer therapy. This review reports the synthesis and Chk1 inhibitory activities of pyrrolocarbazole compounds bearing four or five fused rings.     

Endophthalmitis after Lasiodiplodia theobromae corneal abscess

Background:Lasiodiplodia theobromae is an exceptional cause of human keratomycosis. Patient: We treated a 53-year-old man with fungal keratitis, which had been treated with topical betamethasone and gentamicin for 1 month, and endophthalmitis due toLasiodiplodia theobromae. Despite intensive systemic, topical and intravitreal fungicidal treatment, enucleation had to be performed. Results: The vitreous aspirate cultures were negative as of the second amphotericin intravitreal injection. However, histology revealed that the fungus was present in the cornea, ciliary body, iris and retina. Conclusion: The use of topical steroids may worsen the outcome of the infection.     

Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF)

OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA. METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis. RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings. CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.     

Rhabdomyosarcoma of the head and neck in adults: A study of 26 patients

The clinical records of 26, predominantly male, adults with rhabdomyosarcomas in the head and neck were analyzed. Patients' ages ranged from 18 to 74 years (mean: 24.5 years). According to the retrospective clinical group classification, 18 (69%) of 26 were advanced tumors at initial presentation belonging to group III or IV. The ethmoids were the most common primary site of origin in 12 (46%) of 26 patients. Nodal and systemic metastases were noted in 12 (46%) and 6 (23%) patients, respectively. Bone metastases were noted in 4 patients. Heterogeneous treatment protocols were used with a variety of chemotherapy combinations in most cases, with surgery and radiotherapy. Overall results were poor, with a survival rate of 7.6% at 5 years. Neither histopathology nor response to chemotherapy was found to influence survival. All long-term survivors belonged to the early-stage groups (clinical groups I and II) for which complete surgical excision was possible. In spite of a poor prognosis after relapse, the use of aggressive chemotherapy appeared to prolong life in some patients.