65 research outputs found
Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells
Glucocorticoids play an important role in the treatment of a number of
hematological malignancies, such as multiple myeloma. The effects of
glucocorticoids are mediated through the glucocorticoid receptor alpha,
the abundance of which can be modulated by alternative splicing of the
glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid
receptor mRNA have been described: glucocorticoid receptor beta, which
reportedly has a dominant negative effect on the actions of the
glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the
effects are unknown. In this study, we have investigated the expression
levels of these two splice variants at the mRNA level in multiple myeloma
cells and in a number of other hematological tumors. Although the
glucocorticoid receptor beta mRNA was, if at all, expressed at very low
levels, considerable amounts (up to 50% of the total glucocorticoid
receptor mRNA) glucocorticoid receptor P mRNA was present in most
hematological malignancies. In transient transfection studies in several
cell types and in multiple myeloma cell lines, the glucocorticoid receptor
P increased the activity of the glucocorticoid receptor alpha. These
results suggest that the relative levels of the glucocorticoid receptor
alpha and the glucocorticoid receptor P may play a role in the occurrence
of glucocorticoid resistance in tumor cells during the treatment of
hematological malignancies with glucocorticoids
Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma
We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mR and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32-65 years; Durie and Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity
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