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Retinoids, the natural and synthetic analogs of vitamin A, are growth-inhibiting and differentiation-inducing agents and show clinical promise as chemopreventive and antineoplastic agents. Fenretinide, a new synthetic retinoid, has antitumor activity in certain in vitro and in vivo model systems and was relatively nontoxic in phase I trials. Based on these data, we designed a phase II study of Fenretinide involving 31 patients with advanced breast cancer [15] and melanoma [16], two cancers shown to be responsive to this agent in preclinical models. Fenretinide was inactive in patients with advanced disease. Toxicity was mild, and reversible. Mucocutaneous side effects occurred in 16 (52%) patients. Nyctalopia developed in three patients one of whom developed decreased B-wave amplitude of the scotopic electroretinogram. The minimal toxicity and significant activity in preclinical studies make this an attractive agent for future breast cancer chemoprevention studies.

BACKGROUND:In middle income countries, the burden of rheumatic heart disease (RHD) remains high, but the prevalence of other heart valve diseases may rise as the population life expectancy increases. Here, we compared population-based data on surgical procedures to assess the relative importance of causes of heart valve disease in Salvador, Brazil. METHODOLOGY/PRINCIPAL FINDINGS:Medical charts of patients who underwent surgery for valvular heart disease from January 2002-December 2005 were reviewed. Incidence of surgery for valvular heart disease was calculated. Logistic regression was used to identify factors associated with in-hospital death following surgery. The most common etiologies for valvular dysfunction in 491 valvular heart surgery patients were RHD (60.3%), degenerative valve disease (15.3%), and endocarditis (4.5%). Mean annual incidence for surgeries due to any valvular heart diseases, RHD, and degenerative valvular disease were 5.02, 3.03, and 0.77 per 100,000 population, respectively. Incidence of surgery due to RHD was highest in young adults; procedures were predominantly paid by the public health sector. In contrast, the incidence of surgery due to degenerative valvular disease was highest among those older than 60 years of age; procedures were mostly paid by the private sector. The overall in-hospital case-fatality ratio was 11.9%. Independent factors associated with death included increase in age (odds ratio: 1.04 per year of age; 95% confidence interval: 1.02-1.06), endocarditis (6.35; 1.92-21.04), multiple valve operative procedures (4.35; 2.12-8.95), and prior heart valve surgery (2.49; 1.05-5.87). CONCLUSIONS/SIGNIFICANCE:RHD remains the main cause for valvular heart surgery in Salvador, which primarily affects young adults without private health insurance. In contrast, surgery due to degenerative valvular disease primarily impacts the elderly with private health insurance. Strategies to reduce the burden of valvular heart disease will need to address the disparate factors that contribute to RHD as well as degenerative valve disease.

Integrin-mediated cellular adhesion to extracellular matrix (ECM) components is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (CML) cells are adhered to fibronectin (FN), they become resistant to apoptosis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA damaging agents and gamma-irradiation. This phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), was induced by adhesion through the alpha5beta1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti-apoptotic signaling through integrins in K562 cells is independent of the tyrosine kinases activated by BCR/ABL, with the possible exception of an unknown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor-ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of beta1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the novel BCR/ABL kinase inhibitors being used for the treatment of this disease. [ABSTRACT FROM AUTHOR]

The tumor cell environment may influence drug response through interactions with the extracellular matrix (ECM). We recently reported that adhesion of myeloma cells to fibronectin (FN) via β1 integrins is associated with a cell adhesion mediated drug resistance (CAM-DR). Activation of β1 integrins is known to influence both apoptosis and cell growth. We hypothesized that the FN mediated cytoprotection may be in part due to perturbations in cell cycle progression. In this report we demonstrate that adhesion of myeloma cells to FN results in a G1 arrest associated with increased p27kip1 protein levels and inhibition of cyclin A and E associated kinase activity. Disruption of cells from FN adhesion resulted in a rapid recruitment of cells into S phase, a decrease in p27kip1 levels, and reversion to a drug sensitive phenotype. Treatment of cells with p27Kip1 antisense oligonucleotides did not affect FN adhesion; however, p27Kip1 protein levels were reduced and cells became sensitive to cytotoxic drugs. These studies demonstrate that β1 mediated adhesion of myeloma cells to FN regulates p27kip1 levels and that p27kip1 levels are causally related to CAM-DR. Disruption of β1 integrin mediated FN adhesion may represent a potential target for the potentiation of drug induced apoptosis. Oncogene (2000) 19, 4319–4327 [ABSTRACT FROM AUTHOR]

CD95 (Fas/APO-1) is a member of the TNFR superfamily that induces apoptosis following cross-linking with its cognate ligand, CD95L (FasL/APO-1L) or agonist antibody. The human myeloma cell line, RPMI 8226, has limited sensitivity to CD95-mediated apoptosis, with a maximum of 65% of the population responding. To determine the source of the limited sensitivity to CD95-mediated apoptosis, we isolated multiple clones from the RPMI-8226 cell line by limiting dilution. Analysis of these clones demonstrated that sensitivity to CD95-mediated cell death directly correlated with CD95 expression. Clones with high levels of CD95 expression had greater than 90% cell death, whereas cells with low levels of expression had less than 10% cell death. In contrast, no correlative differences were identified for other members of the DISC complex, or for members of the anti-apoptotic Bcl-2 family. We further examined the sensitivity of the 8226 clones to various cytotoxic agents. Although modest clonal variability was demonstrated in response to the chemotherapeutic drugs, doxorubicin, etoposide (VP-16), and vincristine, there was no correlation between CD95 function and sensitivity to chemotherapeutic drugs. These results indicate that in this cell line, receptor expression is rate limiting in CD95-mediated apoptosis, whereas CD95 expression was not a determinant in drug-induced programmed cell death. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a disease which is generally considered responsive to chemotherapy; however, essentially all patients who respond to drug treatment will relapse and die of drug-resistant disease. This disease is therefore considered a paradigm for studying the development of acquired drug resistance in the clinic. Natural product agents are frequently used in the treatment of myeloma, especially vincristine and doxorubicin. Studies using human myeloma cell lines have shown that the MDR1 gene product, P-glycoprotein (Pgp), is responsible for conferring drug resistance to natural products and glucocorticoids. We have developed assays to measure the expression of MDR1/Pgp in human myeloma specimens. These assays include immunocytochemistry, flow cytometry, and RT/PCR. Human myeloma cell lines, 8226/Dox, that are resistant to natural product agents and overexpress MDR1/Pgp are important for standardizing results and offer a means of comparing inter- and intra-patient results. Assays which measure both the presence and function of Pgp are necessary to determine the role of Pgp in clinical drug resistance in patients with myeloma. [ABSTRACT FROM AUTHOR]