RALBP1/RLIP76 mediates multidrug resistance.

RLIP76/RALBP1 is a multi-specific drug-transporter which can mediate drug-resistance in lung and other cancers, but its ability to mediate multidrug-resistance has not been previously demonstrated in hematological malignancy. Present studies in K562 human myelogenous leukemia show that RALBP1 overexpression confers broad resistance to multiple chemotherapy drugs including cisplatin, melphalan, doxorubicin, daunorubicin, vincristine, vinblastine, vinorelbine, and mitomycin-C. Conversely, inhibition of RALBP1 by polyclonal antibodies causes increased drug-accumulation and increased cytotoxicity. These studies demonstrate the potential utility of targeting RALBP1 in the treatment of leukemia.

RLIP76 is a major determinant of radiation sensitivity.

RLIP76 (RALBP1) is a glutathione-conjugate transporter that is a critical component of clathrin-coated pit-mediated endocytosis, as well as in stress responses. In cultured cells, it provides protection from stressors including heat, oxidant chemicals, chemotherapeutic agents, UV irradiation, and X-irradiation. Here, we show marked reduction in glutathione conjugate transport capacity and stepwise increase in radiation sensitivity associated with heterozygous or homozygous loss of the RLIP76 gene in mice. Survival after radiation in homozygous knockout animals was significantly shorter than either the heterozygous knockouts or the wild type. Delivery of recombinant RLIP76 to mice lacking RLIP76 via a liposomal delivery system rescued radiation sensitivity. Furthermore, treatment of wild-type mice with RLIP76-containing liposomes conferred resistance to radiation. These findings suggest that inhibiting RLIP76 could be used for sensitization to radiation during cancer therapy and that RLIP76 liposomes could be radioprotective agents useful for treatment of iatrogenic or catastrophic radiation poisoning.

Therapeutic resistance in lung cancer.

Despite considerable progress over the last 25 years in the systemic therapy of lung cancer, intrinsic and acquired resistance to chemotherapeutic agents and radiation remains a vexing problem. The number of mechanisms of therapeutic resistance in lung cancer has expanded considerably over the past three decades, and the crucial role of stress resistance pathways is increasingly recognised as a cause of intrinsic and acquired chemo- and radiotherapy resistance. This paper reviews recent evidence for stress defence proteins, particularly RALBP1/RLIP76, in mediating intrinsic and acquired chemotherapy and radiation resistance in human lung cancer.

Impact of medication adherence on health care utilization and productivity: self-reported data from a cohort of postmenopausal women on osteoporosis therapy.

BACKGROUND: Many pharmacologic agents are approved for the prevention and treatment of osteoporosis, which is common among postmenopausal women. Evidence exists relating treatment persistence to fracture risk. Less is known about treatment persistence and the use of health care service and individual productivity. OBJECTIVE: This study was undertaken to describe health care use and productivity loss relative to osteoporosis medication persistence using women's self-reported data from the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US™), a large, longitudinal (October 2004-December 2009) osteoporosis cohort study of postmenopausal women. METHODS: Analyses included women on pharmacologic osteoporosis therapy (alendronate, risedronate, ibandronate, calcitonin, raloxifene, or teriparatide) who provided health care use/productivity data collected using semiannual questionnaires over 1 year of follow-up. Participant characteristics, use, and productivity metrics were summarized. Logistic regression models and generalized linear models were used to examine use, time missed from usual activities, number of days spent in bed, and lost work time relative to treatment persistence, adjusting for potential confounders. RESULTS: At entry, of the 2528 women studied (91% white, 3.1% Hispanic/Latino, 2.3% African American/black, 1.1% Asian, and 2.1% American Indian/Native Alaskan, Native Hawaiian/Pacific Islander, or other; mean age, 64.6 [range, 37-97] years), 43.1% had osteoporosis and 23.4% had a previous fracture. After adjustment, subjects who switched therapies during follow-up were more likely to have had any kind of diagnostic testing (95.2% of switchers vs 91.2% of persistent subjects and 88.9% of discontinuers, P < 0.05). Discontinuers were less likely than persistent subjects to visit their primary care physicians (92.0% vs 94.4%, P = 0.0337). Variations in the number of days spent in bed, time missed from usual activities, and work loss (n = 852 employed subjects) by treatment persistence were not significant. CONCLUSIONS: Use of diagnostic testing differed significantly by osteoporosis treatment status. Compared with women who persisted with treatment, primary care provider visits were less common among those who discontinued treatment. Treatment persistence was not associated with significant differences in productivity measures.