Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.

No abstract

Anemia as associated with numerous clinical conditions can be debilitating, but frequently can be treated via administration of epoetin-alfa, darbepoietin-alfa, or methoxy-PEG epoetin-beta. Despite the complexity of EPO-EPO receptor interactions, the development of interesting EPO mimetic peptides (EMPs) also has been possible. CNTO 530 is one such novel MIMETIBODY Fc-domain dimeric EMP fusion protein. In a mouse model, singledose CNTO 530 (unlike epoetin-alfa or darbepoietin-alfa) bolstered red cell production for up to 1 month. In 5-fluorouracil and carboplatin-paclitaxel models, CNTO 530 also protected against anemia with unique efficiency. These actions were not fully accounted for by half-life estimates, and CNTO 530 signaling events therefore were studied. Within primary bone marrow erythroblasts, kinetics of STAT5, ERK, and AKT activation were similar for CNTO 530 and epoetin-alfa. p70S6K activation by CNTO 530, however, was selectively sustained. In vivo, CNTO 530 uniquely stimulated the enhanced formation of PODXL high CD71 high (pro)erythroblasts at frequencies multifold above epoetin-alfa or darbepoietin-alfa. CNTO 530 moreover supported the sustained expansion of a bone marrow-resident Kit neg CD71 high Ter119 neg progenitor pool. Based on these distinct erythropoietic and EPOR signaling properties, CNTO 530 holds excellent promise as a new EPO mimetic. IntroductionAs recombinant injectables, epoetin-alfa and darbepoietin-alfa are important therapeutics for anemia. 1,2 Via its canonical dimeric single-transmembrane receptor (EPOR), 3,4 and possibly a hypothesized accessory chain, 5,6 erythropoietin (EPO) also has been shown to confer significant cytoprotection for certain injured nonhematopoietic tissues. 7 This includes renal, cardiac, brain, and retinal cells as damaged by ischemia, neurotoxins, or UV irradiation. [8][9][10][11] However, epoetin-alfa can require frequent injections in anemia contexts, as well as relatively high dosing to cytoprotect nonhematopoietic cells. 7 To address these issues, several EPOrelated erythropoiesis stimulating agents (ESAs) recently have been formulated and shown to possess one, or another, advantaged property. One orthologue is darbepoietin-alfa in which nonessential residues are mutated to provide for 2 additional N-linked glycosylation sites. 12 This can enhance darbepoietin-alfa's in vivo halflife, 13 and EPO receptor occupancy. 14 Together, these properties can lessen dosing frequency. 13 A second example is provided by "Epo-Epo" in which EPO is configured as a peptide-linked head-to-tail dimer. 15 For Epo-Epo, unique properties include enhanced secretion and apparent advantaged in vivo activity after subcutaneous injection. 16 In addition, a pegylated epoetin-beta has been developed (CERA) that possesses a significantly extended half-life, 17 and likewise can be effectively used with less frequent dosing. 18 A distinct approach to preparing ESAs involves the development of monoclonal antibodies that can bind and activate the EPOR. In particular, Liu et al 1...

No abstract

No abstract