Molecular cytogenetic studies were conducted on three multidrug-resistant cancer sublines which are highly resistant to the chemotherapeutic agent mitoxantrone, an anthracenedione. The three independently selected sublines were derived by exposure to mitoxantrone or Adriamycin and do not overexpress MDR1 or MRP. Two sublines, MCF-7 AdVp3000 and MCF-7 MX, showed an amplification peak at 4q21-q22, as demonstrated by comparative genomic hybridization (CGH), while the third, S1-M1-80, did not. FISH using a whole chromosome 4 paint demonstrated multiple rearrangements involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX, while S1-M1-80 contained only a simple reciprocal translocation. The parental cell lines had no chromosome 4 rearrangements and no copy number gain or amplification of chromosome 4. Spectral karyotyping (SKY) analysis revealed a balanced translocation, t(4;17)(q21-q22;p13) in S1-M1-80 and multiple clonal translocations involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX. A novel cDNA, designated MXR, which encodes an ABC half-transporter and is highly overexpressed in the three sublines, was localized to chromosome 4 by somatic cell hybrid analysis. Southern blot analysis demonstrated amplification of the MXR gene in MCF-7 AdVp3000 and MCF-7 MX, but not in S1-M1-80. FISH studies with a BAC probe for MXR localized the gene to 4q21-22 in the normal chromosome 4 and revealed in both MCF-7 AdVp3000 and MCF-7 MX amplification of MXR at one translocation juncture, shown by SKY to be t(4;5)(4qter-->4cen-->4q21-22::5q13-->5qter++ +) in MCF-7 AdVp3000 and t(6;4;6;3)(6pter-->6q15::4q21-q22::hsr::6q?::3q?27-->+ ++3qter) in MCF MX; neither of the breakpoints in the partner chromosomes showed amplification by CGH. The data are consistent with the hypothesis of a transporter, presumably that encoded by the MXR gene, mediating mitoxantrone resistance. The MXR gene encodes a half-transporter and the absence of cytogenetic evidence of coamplification of other regions suggests that a partner may not be overexpressed, and instead the MXR half-transporter homodimerizes to mediate drug transport. Genes Chromosomes Cancer 27:110-116, 2000. Published 2000 Wiley-Liss, Inc.
Effective local ablation of large tumors with radiofrequency has been made possible by recent advancements. Tumor ablation with radiofrequency has been described mainly in the liver, but also recently in the kidney, adrenal gland, lung, and breast. A rapidly growing splenic metastasis from renal cell carcinoma was effectively treated percutaneously, with US guidance. Focal splenic disease may not be a common indication for ablation; however, further work is necessary to evaluate the safety and efficacy of this procedure in this setting.
1657 Poster Board I-683 Background The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel pan-HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with cutaneous T-cell lymphoma (CTCL) in two phase 2 studies. Aims To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and CTCL. Methods This Phase 2, open-label, multi-arm, multicenter study enrolled 46 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. This study is now closed to accrual. Pts with relapsed or refractory PTCL who had received at least one prior standard chemotherapy regimen were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results 46 pts (24 [52%] men and 22 [48%] women) with a mean age of 59 (range: 28 to 84) years were treated with romidepsin. 32 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 4.8 (range 1 to 14). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1-47) and the overall median duration of response was 9.0 months (range 1.8 months to 5.8 yrs) for all pts. The median duration of response for the 5 pts who achieved CR was 6.0 months (range 2.8 months to 5.8 yrs).The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (74%; 9% ≥grade 3), fatigue (72%; 20% ≥grade 3), decreased platelets (72%; 35% ≥grade 3), cardiovascular/general-other (72%; 0% ≥grade 3) and decreased AGC (65%; 43% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions This study demonstrates tolerability and durable clinical benefit (ORR of 33% and median duration of response of 9.0 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with relapsed or refractory PTCL is ongoing at multiple international centers. Disclosures Kirschbaum: Gloucester Pharmaceuticals: Consultancy.
We conclude that approximately one in 20 Australians aged 50 years or over harbours a paraprotein, a prevalence that appears higher than from similar cohorts in other countries.
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