The shape of the messenger: using protein structure information to design novel cytokine-based therapeutics

The cloning and mass production of recombinant cytokine proteins opened a new world of treatment possibilities. While some cytokines, including several haematopoietic factors and interferons, are now used routinely in the clinic, there are still many problems with side effects. These are due to the many different activities of cytokines on different cell populations. In some cases, activities responsible for side effects have been attributed to discreet areas of the proteins and "structure driven design" can be used to generate novel proteins with better clinical profile. In other cases, structural alterations can enhance activity by increasing serum half-life. This review summarizes the structures of cytokines and their receptor complexes deposited in the Protein Data Base (PDB) and introduces the other articles in this issue on structure-driven design of cytokines for therapy. Cytokines fall into only a few structural classifications. Most of the growth regulatory cytokines including serum factors, growth hormone, haematopoietic growth factors, colony stimulating factors, erythropoietin, IL-3, IL-2 and interferons, are four or five helix bundles. Factors which primarily induce inflammatory responses, including TNF, lymphotoxin and IL-1, form beta-barrel structures that resemble the FGF family. Chemokines and factors that regulate multicellular responses, such as macrophage migration, neutrophil invasion and chemotaxis, have similar structures, classified as alpha + beta. One biological paradox is that many cytokines that vary greatly in function have a similar structure and share receptors. However, homologous cytokines may differ considerably in their mode of interaction with a shared receptor. A few structures for the extracellular regions of cytokine receptors are known, in several cases complexed with their biological target. These structures, coupled with structural alignment of families, indicate areas that control binding to receptors, as opposed to specific areas responsible for the specific activities of this diverse group of proteins. Methods to use cytokine structure to derive better therapeutics are summarized.     

Comment on ‘Predicting recurrence in axillary node negative breast cancer patients’, by Rosner and Lane

on behalf of the Nottingham Breast Unit     

Neural and musculoskeletal contributions to the development of stance balance control in typical children and in children with cerebral palsy

Studies on the development of automatic postural responses in both typically developing children and children with cerebral palsy were performed. With the appearance of "pull-to-stand" behavior, typically developing children first began to show muscle responses to platform movements in mainly the ankle muscles. With increased development, additional agonist muscles were added to the response pattern and a consistent distal to proximal sequence began to emerge. Well-organized responses were seen with the onset of independent stance and walking, along with the reduction of antagonist muscle co-activation. The older children with cerebral palsy who were pre-walkers had immature muscle activation patterns like those seen in the typically developing children at the pull-to- stand stage of development. These included disorganized muscle responses and increased frequency of coactivation of both proximal–distal and agonist–antagonist muscles. In order to determine if musculoskeletal constraints contributed to these response patterns, normal children were asked to stand in a crouched posture similar to that of children with CP. This caused postural muscle response patterns to more closely approximate those of children with spastic diplegia.     

A Phase II trial of high-dose intravenous interferon alpha-2 in advanced colorectal cancer

Twenty-one patients with metastatic colorectal cancer were treated with high-dose intravenous interferon alpha-2 (30-50 X 10(6) units/m2) administered daily for 5 consecutive days. Courses of therapy were repeated every 2 to 3 weeks. No tumor responses were seen among 15 evaluable patients. In two subjects, disease remained stable for 3 and 7 months, respectively. Toxicity was substantial and a de-escalation of dose was frequently required. Fevers, gastrointestinal symptoms, fatigue, leukopenia, and elevated serum transaminases were common. High-dose interferon was found to be ineffective in the treatment of metastatic colorectal cancer. A daily dose of 50 X 10(6) units/m2 was greater than the maximum tolerated dose in this group of patients.     

Billroth in Zurich.

Billroth came to the Kantonspital in Zurich as a disciple of v. Langenbeck. He changed that hospital from a largely privately controlled and state-dominated chronic disease hospital to an active teaching center with full-time personnel, a residency system, and its own equipment. He instituted a system of follow-up surgical statistics and criteria for certain surgical procedures. His technical ability and scholarship in pathology, anatomy, and surgical techniques made that institution a sought-after school. The marked swings in moods that were to characterize Billroth's entire career started in Zurich and had their source in his musical, professional, and personal interrelationships. Most important, this apprenticeship in surgery and administration made it possible for him, after 7 years, to be accepted to the Professorship at the University of Vienna, at that time the outstanding surgical school on the continent.