Immunoglobulin isotypes in multiple myeloma: laboratory correlates and prognostic implications in total therapy protocols.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA, and Cancer Research and Biostatistics, Seattle, WA, USA. E-mail: .
British Journal of Haematology (Impact Factor: 4.96). 04/2009; 145(1):134-7. DOI: 10.1111/j.1365-2141.2008.07547.x
Source: PubMed
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    ABSTRACT: This study was done to observe the alteration of the estimated glomerular filtration rate (eGFR) in multiple myeloma patients according to type of tandem hematopoietic stem cell transplantation (HSCT). Forty-one patients were enrolled in this study. Twenty patients underwent autologous HSCT (auto-HSCT) and 21 patients underwent allogeneic HSCT (allo-HSCT). The changes in eGFR after the two tandem HSCT modalities were different between the two groups, according to the donor of stem cells (P = 0.016). In the auto-HSCT group, the eGFR, recorded 12 months after secondary HSCT, was significantly decreased compared with the eGFR recorded before stem cell mobilization (P = 0.005). Although there was no significant difference, the trend showed that the eGFR after allo-HSCT decreased from the previous HSCT until a month after secondary HSCT. In addition, after 6 months of secondary HSCT, the eGFR recovered to the level recorded prior to the HSCT (P = 0.062). This difference may be due to total body irradiation, a calcineurin inhibitor, or maintenance therapy. Changes in renal function would be monitored closely for these patients. The recovery of the eGFR would be a main focus for the patients treated with the total body irradiation or the calcineurin inhibitor, a progressive decline of the eGFR would be also crucial for the patients treated with maintenance therapy.
    Journal of Korean medical science 10/2011; 26(10):1310-5. DOI:10.3346/jkms.2011.26.10.1310 · 1.25 Impact Factor
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    Revista Brasileira de Hematologia e Hemoterapia 01/2013; 35(3):201-17. DOI:10.5581/1516-8484.20130050
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    ABSTRACT: The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR. Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.


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