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Symposium: Innate Immunity and Human Milk

HAMLET Kills Tumor Cells by Apoptosis: Structure, Cellular Mechanisms, and Therapy^1,2

Lotta Gustafsson, Oskar Hallgren, Ann-Kristin Mossberg, Jenny Pettersson, Walter Fischer, Annika Aronsson^* and Catharina Svanborg³

Institute of Laboratory Medicine, Department of Microbiology, Immunology and Glycobiology, ^* Department of Dermatology and Venereology, Lund University, Sweden; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway

³To whom correspondence should be addressed. E-mail: catharina.svanborg{at}med.lu.se.

New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human -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, -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.

KEY WORDS: • tumor • apoptosis • human milk • lactalbumin • protein folding

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