Treatment options in Waldenstrom's macroglobulinemia

Waldenstrom's macroglobulinemia (WM) is a rare chronic B-cell lymphoproliferative disorder characterized by macroglobulin (immunoglobulin M; IgM) paraproteinemia. The clinical manifestations associated with WM can be related to those of direct organ tumor infiltration, hyperviscosity and tissue deposition of IgM. Treatment must be individualized according to the nature of the clinical manifestations. Plasmapheresis has a role in patients whose symptoms are caused by increased serum viscosity. Chlorambucil was first used with response rates varying between 31% and 72% and is now probably the most commonly used oral agent. Melphalan and cyclophosphamide may have similar clinical efficacy. The addition of corticosteroids does not seem to increase response rates and the use of combination chemotherapy in the first-line setting is not recommended. Fludarabine and cladribine are cross-resistant and induce a response in 30%-60% of patients who have had prior therapy with alkylating agents and as many as 100% of previously untreated patients. Thirty-five percent to 50% of patients respond to single rituximab therapy, with limited toxicity. There are no data from prospective randomized studies to guide the choice between alkylating agents, nucleoside analogues, and rituximab for first-line therapy of WM. Autologous and allogeneic stem cell transplantation may be considered for patients with primary refractory/relapsing disease, especially in the younger age groups. Thalidomide alone or in combination with steroids/clarithromycin may be a useful salvage regimen for some heavily pretreated patients with cytopenia, even though toxicity is considerable. Splenectomy is rarely indicated.     

Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases

Structural analogues of nucleosides, nucleoside analogues (NA), are used in the treatment of cancer and viral infections. Antiviral NAs inhibit replication of the viral genome, whereas anticancer NAs inhibit cellular DNA replication and repair. NAs are inactive prodrugs that are dependent on intracellular phosphorylation to their pharmacologically active triphosphate form. The deoxyribonucleoside kinases (dNK) and ribonucleoside kinases (rNK) catalyze the first phosphorylation step, converting deoxyribonucleosides and ribonucleosides to their corresponding monophosphate form. The dNKs have been studied intensively, whereas the rNKs have not been as thoroughly investigated. This overview is focused on the substrate specificity, tissue distribution, and subcellular location of the mammalian dNKs and rNKs and their role in the activation of NAs.     

Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers

Alterations in TGF-beta signaling appear to be associated with an altered risk of developing cancer, including breast cancer. We carried out a case-control study on 8 polymorphisms, including 5 in the TGF-beta1 gene (G-800A, C-509T, Leu10-->Pro, Arg25-->Pro and Thr263-->Ile), a polyalanine polymorphism (9A-->6A) in the TGF-betaRI gene and 2 (G-875A and A-364G) in the TGF-betaRII gene, using samples from 2 different populations, Polish familial and Finnish unselected breast cancer cases, together with ethnically and geographically matched controls. Additionally, familial breast cancer cases with respective controls from Sweden and Germany were studied in the Leu10-->Pro polymorphism, making the total number of familial cases 659. Allele, genotype and haplotype analysis on the TGF-beta1 gene as well as an analysis of the combinations of genotypes of the TGF-beta1 and its receptor genes in each individual were performed. Population differences in the allele and genotype distributions were found from 5 of the polymorphisms and 3 common haplotypes from the TGF-beta1 gene between the Finnish and other populations. However, no statistically significant difference between the breast cancer and healthy control groups was found for any of the 8 polymorphisms nor did the haplotype or genotype combination analysis reach statistical significance. Thus, none of the studied polymorphisms from the TGF-beta1 and its receptor genes was found to influence significantly susceptibility to breast cancer. The possible contribution of 6A/6A homozygosity in the TGF-betaRI gene to breast cancer needs to be confirmed in an independent study.     

Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth

The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of malignant cells, and has emerged as a general and promising target for cancer treatment. However, no fully selective IGF-1R inhibitors have thus far been found. This is explained by the fact that IGF-1R is highly homologous to the insulin receptor, coinhibition of which may cause diabetic response. The receptors are both tyrosine kinases, and their ATP binding sites are identical, implying that ATP inhibitors cannot discriminate between them. Therefore, the current strategy has been to identify compounds interfering with receptor autophosphorylation at the substrate level. In this study we investigated the effects of cyclolignans and related molecules on IGF-1R activity. We report that certain cyclolignans are potent and selective inhibitors of tyrosine phosphorylation of the IGF-1R. Of particular interest was picropodophyllin (PPP), which is almost nontoxic (LD(50) >500 mg/kg in rodents). PPP efficiently blocked IGF-1R activity, reduced pAkt and phosphorylated extracellular signal regulated kinase 1 and 2 (pErk1/2), induced apoptosis in cultured IGF-1R-positive tumor cells, and caused complete tumor regression in xenografted and allografted mice. PPP did not affect the insulin receptor or compete with ATP in an in vitro kinase assay, suggesting that it may inhibit IGF-1R autophosphorylation at the substrate level. This is also in agreement with our molecular model of how the cyclolignans may act on the IGF-1R kinase. Our results open the possibility to use PPP or related compounds with inhibitory effects on IGF-1R as lead compounds in development of anticancer agents.     

Trichomonas vaginalis among HIV-Infected women: are immune status or protease inhibitor use associated with subsequent T. vaginalis positivity?

BACKGROUND AND OBJECTIVES: Trichomonas vaginalis (Tv) is a common sexually transmitted disease (STD) among HIV-infected populations. The relationship between Tv and immune status and HIV viral load as affected by protease inhibitor (PI) use has not been well examined. GOAL: The goals were to evaluate the association between Tv and both immune status and PI use among HIV-infected women, and to characterize factors associated with Tv among HIV-infected women. STUDY DESIGN: We used a retrospective cohort study conducted between 1990 and 2000. RESULTS: Of 1578 women, the majority was under 35 years, black (AA), and infected heterosexually or with unidentified risk. Thirty percent (30.2%) had Tv at least once, and 36.9% had at least one subsequent positive test; Tv was more common than chlamydia, gonorrhea, genital warts, or syphilis. After adjusting for follow-up time, young age, AA race, substance use, and other sexually transmitted diseases (STDs) were associated with initial Tv infection, but pregnancy, immune status, and PI use were not associated. After adjusting for follow-up time, having other STDs was associated with and pregnancy was protective of subsequent Tv positivity, but immune status and PI use were not associated; neither were age, race, or substance use. CONCLUSION: Tv is a common STD among HIV-infected women and does not appear to be associated with immune status or PI use. Aggressive screening might represent a means of reducing the incidence and prevalence of Tv.     

Functional evaluation of cerebral microembolization in the rat

This study investigates the effects of cerebral microembolism on motor performance and risk assessment behavior in the rat. Cerebral infarcts were produced in rats by injecting small plastic beads into the left heart ventricle under short-acting anesthesia. The functional outcome was tested 24 h later by subjecting the animals to a series of consecutive behavioral tests. Thereafter, the rats were anesthetized and underwent magnetic resonance imaging. On average about seven infarcts per brain were found. The volume of the individual infarcts was largest in the hippocampus (mean=4.26 mm(3)) and smallest in the white matter (mean=0.83 mm(3)). Embolized animals performed spontaneous and evident locomotion. The activity was, however, significantly decreased compared to rats treated with vehicle. More specific tests for motor ability revealed reduced gait capacity and muscular strength. A significant relationship was found between behaviors reflecting motor ability and the total volume of infarcted tissue in the brain stem, cortex and cerebellum. Also the behavioral profile of risk and benefit assessment was found to be altered by the microembolization. It is concluded that the combination of the microembolization method and behavioral tests provides a valuable tool for further studies of the pathophysiology of, and potential treatment for, cerebral infarction.