No abstract

HAMLET (human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of apo α-lactalbumin and oleic acid, formed in casein after low pH treatment of human milk. This study examined if HAMLET-like complexes are present in casein from different species and if isolated α-lactalbumin from those species can form such complexes with oleic acid. Casein from human, bovine, equine and porcine milk were separated by ion exchange chromatography and active complexes were only found in human casein. This was not explained by α-lactalbumin sequence variation, as purified bovine, equine, porcine and caprine α-lactalbumins formed complexes with oleic acid with biological activity similar to HAMLET. We conclude that structural variation of α-lactalbumins does not preclude the formation of HAMLET-like complexes and that natural HAMLET formation in casein was unique to human milk, which also showed the highest oleic acid content.

No abstract

New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.

A series of C,C-diacetylenic phosphaalkenes 1b-e has been prepared from 1-chloropenta-1,2-dien-4-ynes 6b-e in a reaction with Mes*PCl(2) (Mes* = 2,4,6-((t)Bu)(3)Ph) in the presence of LDA. Under identical conditions, isomeric butadiyne-substituted phosphaalkenes 2c-f can be obtained from 3-chloropenta-1,4-diynes 5c-f. The title compounds represent rare examples of diethynylethenes in which a constituting methylene has been replaced by a phosphorus center. The formation of both isomers can be rationalized by a common pathway that involves isomeric allenyllithium species. Spectroscopic, electrochemical, and theoretical investigations show that the phosphorus heteroatoms are an intrinsic part of the compounds' pi-systems and lead to decreased HOMO-LUMO gaps compared to those in all-carbon-based reference compounds.