Cryosurgery—a putative approach to molecular-based optimization q John G. Baust, a, * Andrew A. Gage, a,b Dominic Clarke, a,c John M. Baust, a,d and Robert Van Buskirk a a The Institute of Biomedical Technology, State University of New York, Binghamton, NY 13902-6000, USA b Department of Surgery, State University of New York, Buffalo, NY 14214, USA c State University of New York, Upstate Medical Center, Syracuse, NY 13210, USA d Department of Bioengineering, State University of New York, Binghamton, NY 13902, USA Received 29 September 2003; accepted 9 January 2004 Abstract Cryosurgery must be performed in a manner that produces a predictable response in an appropriate volume of tissue. In present-day clinical practice, that goal is not always achieved. Concerns with cryosurgical techniques in cancer therapy focus in part on the incidence of recurrent disease in the treated site, which is commonly 20–40% in metastatic liver tumors, and prostate cancers. Whether the cause of this failure is disease-based or technique related, cryosurgery for cancer commonly needs the support of adjunctive therapy in the form of anti-cancer drugs or radiotherapy to increase the rate of cell death in the peripheral zone of the therapeutic lesion where cell survival is in balance for several days post-treatment. Recent evidence has identified a third mechanism of cell death associated with cryosurgery. This mechanism, apoptosis or gene regulated cell death, is additive with both the direct ice-related cell damage that occurs during the operative freeze–thaw intervals and coagulative necrosis that occurs over days post-treatment. In this manuscript we discuss, through a combination of literature review and new data, the combined roles of these distinct modes of cell death in a prostate and colorectal cancer. Data are presented suggesting that sub-freezing temperatures, when sequentially applied with low dose chemotherapy, may provide improved cancer cell death in the freeze zone periphery. Since the mechanism of action of most common chemotherapeutic agents is to initiate apoptosis in cancer cells, the observation that sub-freezing exposures yields a similar effect provides a possible route toward molecular- based procedural optimization to improve therapeutic outcome. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Tumor therapy; Cryosurgery; Persistent disease; Imaging techniques; Adjunctive therapy; Chemotherapy; Prostate cancer; Colorectal cancer; Apoptosis Cryosurgical treatment of cancer has been in use for many years. Between 1845 and 1851 James Arnott used the technique to freeze cancers in q This work was funded by institutional sources. * Corresponding author. Fax: 1-607-777-2803. E-mail address: jgbaust@binghamton.edu (J.G. Baust). 0011-2240/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cryobiol.2004.01.005 Cryobiology 48 (2004) 190–204 www.elsevier.com/locate/ycryo