Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase. In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture and possibly with ageing and tumorigenesis in vivo. In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres. Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations--a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers.

The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m 2 compared with 1.0 mg/m 2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted marketing approval to Millennium Pharmaceuticals on May 13, 2003 for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m 2 administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.

Purpose:This article summarizes data submitted to the U.S. Food and Drug Administration for marketing approval of azacitidine as injectable suspension (Vidaza, Pharmion Corporation, Boulder, CO) for treatment of patients with myelodysplastic syndrome. Experimental Design: In one phase 3 controlled trial, 191 study subjects were randomized to treatment with azacitidine or to observation; an additional 120 patients were treated with azacitidine in two phase 2 single arm studies. The primary efficacy end point was the overall response rate, defined as complete or partial normalization of peripheral blood counts and bone marrow blast percentages for at least 4 weeks. Results: In the controlled trial, the overall response rate was 15.7% in the azacitidine treatment group; there were no responders in the observation group (P < 0.0001). Response rates were similar in the two single arm studies. During response patients stopped being red cell or platelet transfusion dependent. Median duration of responses was at least 9 months. An additional 19% of azacitidine-treated patients had less than partial responses, most becoming transfusion independent. The most common adverse events attributed to azacitidine were gastrointestinal, hematologic, local (injection site), and constitutional. There were no azacitidine-related deaths. Conclusions: On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Full prescribing information is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome.

Purpose: On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil®; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval. Experimental Design: The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of ≧5 × 10⁶ CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or ≧6 × 10⁶ CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM. Results: The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of ≧5 × 10⁶ CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of ≧6 × 10⁶ CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia. Conclusions: This report describes the Food and Drug Administration review supporting the approval of plerixafor.