Livin, also called melanoma inhibitor of apoptosis protein (IAP) or kidney IAP, is a member of the IAP family of caspase inhibitors that selectively binds the endogenous IAP antagonist SMAC and caspase-3, caspase-7, and caspase-9. As such, Livin inhibits apoptosis, and its overexpression renders malignant cells resistant to chemotherapy. Therefore, inhibitors of Livin could be useful adjuncts to chemotherapy in the treatment of malignancies. This review will discuss Livin as a potential therapeutic target and strategies for its inhibition, including antisense oligonucleotides, small-molecule inhibitors, and immune-mediated approaches. [Mol Cancer Ther 2007;6(1):24 -30]

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Summary The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg‐FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12·8%) and t(4;14) in 15 of 120 (12·5%) patients. Progression‐free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression‐free (median 9·9 months vs. 25·8 months; P = 0·0003) and overall survivals (median 18·3 months vs. 48·1 months; P < 0·0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, β‐2 microglobulin, C‐reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression‐free survival and overall survival. Our results indicate that the t(4;14) detected by cIg‐FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant.

We investigated the relevance of p53 deletions to the clinical outcome of patients with multiple myeloma (MM) treated with highdose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by fluorescence in situ hybridization in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (P ‫؍‬ .0062) and creatinine (P ‫؍‬ .013) levels, but there were no association with patient age, gender, ␤ 2 -microglobulin, C-reactive protein, hemoglobin, albumin or bone lytic lesions, or immunoglobulin isotype. There were no associations of p53 deletions with 13q deletions or translocations t(11;14) or t(4;14). Patients with p53 deletions had significantly shorter progression-free (median, 7.9 versus 25.7 months, P ‫؍‬ .0324) and overall survival (median, 14.7 versus 48.1 months, P ‫؍‬ .0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression-free (P ‫؍‬ .0009) or overall survival (P ‫؍‬ . Introductionp53, a tumor suppressor gene, is implicated in the regulation of cell proliferation, differentiation, and apoptosis. 1 Inactivation of p53 inactivation by mutation or allelic loss has been observed in various human neoplasms and associated with tumor progression. 2,3 In multiple myeloma (MM), p53 mutations are rare and may represent late events in myeloma progression. [4][5][6] The frequency of p53 deletions detected by fluorescence in situ hybridization (FISH) is reported to range from 9% to 34% of MMs. [7][8][9][10] The p53 gene deletions are associated with poor survival in patients with MM treated with conventional chemotherapy regimens, 7,8,10 but there is little information on the relevance of p53 deletions to survival of patients with MM treated with autologous stem cell transplantation (ASCT).We recently reported that t(4;14) but not t(11;14) is an adverse prognostic factor in patients with MM undergoing ASCT. 11 The current study extends our experience of cytoplasmic light-chain immunofluorescence combined with FISH (cIg-FISH) to investigate the frequency and prognostic significance of p53 deletions in a single institutional cohort of patients with MM treated with high-dose chemotherapy followed by autologous stem cell support. Study design PatientsBetween January 1998 and December 2001, 128 consecutive patients were diagnosed and treated for MM with high-dose chemotherapy followed by ASCT at the Princess Margaret Hospital/University Health Network. Informed consent was provided by the patients in this study. The clinical and biologic features were previously reported. 11 Karyotypic analysis was not routinely performed during this study period. All patients received 4 to 5 cycles of the VAD regimen (vincristine, Adriamycin [doxorubicin], and dexamethasone) followed by stem cell mobilization with cyclophosphamide 2.5 g/m 2 and granulocyte colony-stimulating factor (G-CSF; 10 g/kg) and 1 course of melphalan 200 mg/m 2 immediately prior to ASCT. ...

Targeting p53 by the small-molecule PRIMA-1 Met /APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1 Met -induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1 Met alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1 Met decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells.

Although the combination of lenalidomide and dexamethasone is effective therapy for patients with relapsed/refractory multiple myeloma, the influence of high-risk cytogenetic abnormalities on outcomes is unknown. This subanalysis of a large, open-label study investigated the effects of the most common unfavorable cytogenetic abnormalities detected by fluorescence in situ hybridization, del(13q), t(4;14), and del(17p13), in 130 evaluable patients treated with this regimen. Whereas patients with either del(13q) or t(4;14) experienced a median time to progression and overall survival comparable with those without these cytogenetic abnormalities, patients with del(17p13) had a significantly worse outcome, with a median time to progression of 2.22 months (hazard ratio, 2.82; P < .001) and median overall survival of 4.67 months (hazard ratio, 3.23; P < .001). Improved therapeutic strategies are required for this subgroup of patients. This study was registered at www. ClinicalTrials.gov as #NCT00179647. (Blood. 2009;114:522-525)

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