Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects.

Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARbeta/delta and PPARgamma) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

Dwarfism and cytochrome P450-mediated C-6 oxidation of plant steroid hormones.

BRs (brassinosteroids) are plant steroid hormones that are essential for normal plant development. The dramatic dwarfism exhibited by mutants in the CYP (cytochrome P450) enzymes involved in BR biosynthesis indicates a role for these hormones in plant growth and development. Since the mid-1990s, collaborative research has been geared towards developing a better understanding of the CYP85 class of CYPs involved in BR biosynthesis in both Arabidopsis and tomato. Some of the most recent observations include the fact that certain CYP85 CYPs catalyse the synthesis of the most bioactive BR, BL (brassinolide). Current evidence suggests that evolution of this function may have occurred independently in different dicotyledonous species. Interestingly, BL accumulates in tomato fruits, highlighting a key role for this hormone in fruit development. At the same time as developing a better understanding of the enzymatic function of these CYPs, we have also carried out experiments towards characterizing where and when these genes are expressed and mechanisms of their regulation. As expected for a hormone involved in growth and development, biosynthetic gene promoter activity is associated with young rapidly growing cells and with fruit development.