Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-hodgkin lymphoma.

Clin Ther. 2009;31P2:2290-2311

Authors: Dennie TW, Kolesar JM

Background: Bendamustine is a mechlorethamine derivative with a purine-like benzimidazole ring, which may enhance its clinical efficacy. Bendamustine was approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) in March 2008 and for the treatment of rituximab-refractory, indolent B-cell non-Hodgkin lymphoma (NHL) in October 2008. Objective: This article reviews the pharmacologic and pharmacodynamic properties of bendamustine, together with data on efficacy and toxicity from trials investigating the use of bendamustine for the treatment of various hematologic malignancies, including CLL, NHL, and multiple myeloma (MM). Methods: MEDLINE and International Pharmaceutical Abstracts (1970-April 15, 2009) were searched using the terms bendamustine, bendamustin, Treanda, Ribomustin, SDX-105, IMET-3393, and Cytostasan. References from relevant articles were also reviewed for additional sources and material. The databases of the American Society of Hematology (2004-2008) and the American Society of Clinical Oncology (1995-2008) were searched for relevant abstracts. Results: Bendamustine is a mechlorethamine derivative with structural similarity to chlorambucil and other drugs from the nitrogen mustard class, as well as a benzimidazole ring, which may act as an antagonist to purines and amino acids. It has good oral bioavailability but has been studied almost exclusively in the intravenous formulation. It undergoes extensive first-pass metabolism by cytochrome P450 1A2 to active metabolites gamma-hydroxy bendamustine and N-desmethyl-bendamustine, but clinical activity appears to be associated primarily with the parent compound. The t((1/2)) of bendamustine is ~40 minutes. While bendamustine has 2 moieties with possible antitumor effect, it is unclear to what extent the benzimidazole ring enhances the efficacy of the drug. Numerous studies including in vitro assays have reported, however, that bendamustine has little cross-resistance with other alkylating agents and remains active even in extensively pretreated patients. FDA approval for use in CLL was based on findings from a randomized, open-label, Phase III study comparing bendamustine with chlorambucil as single-agent therapy in treatmentnaive patients with CLL (Binet stage B or C). Bendamustine was administered intravenously at a dose of 100 mg/m2 on days 1 and 2, while chlorambucil was administered orally at 0.8 mg/kg daily, both over 4-week cycles for up to 6 cycles. At interim analysis (the data used for FDA approval), bendamustine was associated with a greater overall response (68% vs 39%; P < 0.001), median progression-free survival (21.7 vs 9.3 months; P < 0.001) and median duration of remission (18.9 vs 6.1 months; P < 0.001) compared with chlorambucil. FDA approval for rituximabrefractory, indolent B-cell NHL followed a Phase III, open-label, single-arm study evaluating bendamustine monotherapy in patients who did not respond to rituximab or had progressive disease within 6 months of rituximab therapy. Bendamustine 120 mg/m(2) was administered intravenously on days 1 and 2 of a 21-day cycle for up to 8 cycles. At interim analysis, the overall response rate was 84%, including 29% complete response. The median progression-free survival was 9.7 months. The efficacy of bendamustine has also been reported in the treatment of MM in clinical studies, and bendamustine has been approved in Europe for treating MM, NHL, CLL, breast cancer, and Hodgkin lymphoma. Dose-limiting toxicity is primarily hematologic. Treatment-associated infections have been reported in some studies; however, nonhematologic adverse events have rarely been dose limiting. The most common nonhematologic adverse events include fatigue, nausea, xerostomia, and pyrexia. Conclusions: Bendamustine is a mechlorethamine derivative with a purine-like benzimidazole ring, which may enhance its clinical efficacy. It has been approved in the United States for the treatment of CLL and rituximab-refractory, indolent B-cell NHL. It has been approved in Europe for use in other malignancies, and clinical studies have reported activity in MM.

PMID: 20110042 [PubMed - as supplied by publisher]

Degarelix: A gonadotropin-releasing hormone antagonist for the management of prostate cancer.

Clin Ther. 2009;31P2:2312-2331

Authors: Steinberg M

Background: Prostate cancer is the most commonly diagnosed cancer among men. Treatment can include surgery, radiation, chemotherapy, or hormonal manipulation. Gonadotropin-releasing hormone (GnRH) analogues are used to manage prostate cancer by desensitizing the stimulus to synthesize and release gonadotropins, such as luteinizing hormone (LH), which stimulate the synthesis and release of androgens, in turn stimulating the growth of prostate cancer cells. Although effective, these agents have limitations, such as a flare-up of cancer symptoms within the first 2 weeks of starting the drug. Objective: This article reviews the pharmacology, pharmacokinetic and pharmacodynamic characteristics, and clinical data available on the newly approved drug degarelix for use in treating prostate cancer. Methods: A search of the medical literature was performed in January 2009 with the databases MEDLINE and EMBASE (1950-present) and International Pharmaceutical Abstracts (1970-November 2008) using the terms degarelix and FE200486; follow-up searches using the same strategy were conducted in May 2009 and August 2009. Additional sources were identified by scanning available references and online journals and textbooks. Results: GnRH antagonists, such as degarelix, offer clinicians another means to reduce the level of circulating androgens and limit this growth stimulus directed at malignant prostate tissue. Degarelix has been shown in animal studies to antagonize GnRH receptors in the pituitary gland, resulting in a significant reduction in circulating LH and a subsequent decrease in the synthesis of testosterone. Pharmacokinetic analysis suggests that upon subcutaneous administration, degarelix forms a gel depot, from which the drug then distributes to the rest of the body in a first-order manner. A Phase II study of the effect of degarelix in 187 men with prostate cancer found a loading dose of 240 mg to be not significantly better than 200 mg in reducing serum testosterone concentrations to </==0.5 ng/mL within 3 days of dosing (200 mg, 88%; 240 mg, 92%). This difference in percentage of patients with testosterone suppression became statistically significant when measured again 1 month into the study (200 mg, 86%; 240 mg, 95%; P = 0.048). Evaluation of 80-, 120-, and 160-mg maintenance doses found all doses effective in maintaining suppression of testosterone, LH, and prostate-specific antigen (PSA); only minor differences were observed during the study period. In a Phase III study of 610 patients with prostate cancer, a loading dose of degarelix 240 mg SC followed by monthly maintenance doses of either 80 or 160 mg was compared with monthly doses of leuprolide 7.5 mg IM. Degarelix was found to be at least as effective as leuprolide in the ability to suppress serum testosterone to </==0.5 ng/mL for up to 1 year (degarelix response rate, 80 mg, 97.2%; 95% CI, 93.5%-98.8%; degarelix 160 mg, 98.3%; 95% CI, 94.8%-99.4%; leuprolide response rate, 96.4%; 95% CI, 92.5%-98.2%). Other studies investigating various doses and schedules of degarelix have also been conducted. Adverse effects of degarelix in clinical trials were mild and relatively uncommon and included flushing reactions, injection-site pain, weight gain, and increases in serum transaminase levels. Conclusions: Degarelix offers another option for chemical castration to reduce the androgenic growth stimulus on prostate cancer cells. The manufacturer of degarelix recommends a loading dose of 240 mg SC followed by the first monthly maintenance dose of 80 mg 28 days later. Serum testosterone and PSA concentrations must be obtained to monitor the response during treatment with degarelix.

PMID: 20110043 [PubMed - as supplied by publisher]

p66Shc-a longevity redox protein in human prostate cancer progression and metastasis : p66Shc in cancer progression and metastasis.

Cancer Metastasis Rev. 2010 Jan 29;

Authors: Rajendran M, Thomes P, Zhang L, Veeramani S, Lin MF

p66Shc, a 66 kDa proto-oncogene Src homologous-collagen homologue (Shc) adaptor protein, is classically known in mediating receptor tyrosine kinase signaling and recently identified as a sensor to oxidative stress-induced apoptosis and as a longevity protein in mammals. The expression of p66Shc is decreased in mice and increased in human fibroblasts upon aging and in aging-related diseases, including prostate cancer. p66Shc protein level correlates with the proliferation of several carcinoma cells and can be regulated by steroid hormones. Recent advances point that p66Shc protein plays a role in mediating cross-talk between steroid hormones and redox signals by serving as a common convergence point in signaling pathways on cell proliferation and apoptosis. This article first reviews the unique function of p66Shc protein in regulating oxidative stress-induced apoptosis. Subsequently, we discuss its novel role in androgen-regulated prostate cancer cell proliferation and metastasis and the mechanism by which it mediates androgen action via the redox signaling pathway. The data together indicate that p66Shc might be a useful biomarker for the prognosis of prostate cancer and serve as an effective target for its cancer treatment.

PMID: 20111892 [PubMed - as supplied by publisher]

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Although the human papillomavirus, known as HPV, is the main cause of developing cervical cancer, the risk increased in those who used oral contraceptives for a long and consistent period of time. The study analyzed more than 12,500 women in 2003 and noted an increased risk of developing cancer of the cervix in women and noted that the risk decreased when the medication was no longer taken.

Too often than not, drugs are approved for national use, only to be recalled weeks or months later due to adverse side effects and symptoms that went unnoticed or repressed from public knowledge. By providing FDA alerts, drug interactions and up to date drug information about prescription and over the counter medications, we can ensure an environment where patients have the best knowledge on their medical treatment and health.



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