Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m(2) ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m(2) , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM.

3,3'-Diindolylmethane increases serum interferon-γ levels in the K14-HPV16 transgenic mouse model for cervical cancer.

UNLABELLED: While cervical cancer incidence and mortality rates have declined in the United States, this cancer represents a worldwide threat. Human papilloma viral infection causes cervical neoplasia (CIN). 3,3'-Diindolylmethane (DIM) prevents or inhibits the progression from cervical dysplasia to cancer. The aim of this study is to determine the most effective dose of DIM given continuously in food, that significantly increases serum interferon gamma levels (IFN-γ) in the K14-HPV16 transgenic mouse model for cervical cancer. MATERIALS AND METHODS: Five doses of DIM in food were administered to the mouse model for 20 weeks. Serum Interferon gamma (IFN-γ) levels and estrogen metabolite levels were quantified. RESULTS: At 1000 ppm DIM, serum IFN-γ concentrations were significantly increased (p<0.0396). The estrogen metabolites were unchanged. IFN-γ concentrations in CIN free mice and the percentage of CIN free transgenic mice were well correlated (r=0.88). DISCUSSION: Significant increases in IFN-γ serum concentrations that correlate with the percentage of CIN free mice in each group indicate that 1000 ppm of DIM in food may be the most effective dose for future studies. These results may eventually lead to new and effective vaccination strategies in women already infected with the human papilloma virus.

Results from a dose-response study using 3,3'-diindolylmethane in the K14-HPV16 transgenic mouse model: cervical histology.

The human papilloma virus is the major cause of cervical cancer. Viral infection initiates cervical intraepithelial neoplasia, which progresses through several stages to cervical cancer. The objective of this study is to identify the minimum effective dose of diindolylmethane that prevents the progression from cervical dysplasia to carcinoma in situ. We document cervical histology in K14-HPV16 mice receiving different doses of diindolylmethane. Urinary diindolylmethane concentrations are reported. Diindolylmethane could enhance the efficacy of human papilloma virus vaccines, creating a new therapeutic use for these vaccines in women already infected with the virus. Five doses (0-2,500 ppm) of diindolylmethane were incorporated into each mouse diet. The reproductive tract was serially sectioned and urine was obtained for analysis of urinary diindolylmethane. The results indicate that 62% of mice receiving 1,000 ppm diindolylmethane remained dysplasia-free after 20 weeks compared with 16% of mice receiving no diindolylmethane and 18% receiving 500 ppm; 1,000 ppm of 3,3'-diindolylmethane in the diet completely suppressed the development of cervical cancer. Urinary diindolylmethane levels increased significantly as diindolylmethane in food increased. These findings imply usefulness for diindolylmethane in the search to prevent cervical cancer when used in combination with prophylactic or therapeutic vaccines.