Heat Shock Proteins in Cancer Therapy
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HEAT SHOCK PROTEINS IN CANCER THERAPY Katalin V. Lukacs1,2, Olivier E. Pardo1, M. Jo Colston3, Duncan M. Geddes1, and Eric WFW Alton 1
National Heart and Lung Institute
Imperial College School of Medicine Manresa Rd., London SW3 6LR 1 Chester Beatty Laboratories Institute of Cancer Research Fulham Rd, London SW3 6JB2 and National Institute for Medical Research The Ridgeway, Mill Hill, NW7 1AA London3
1. HEAT SHOCK PROTEINS Heat shock proteins (hsps) are ubiquitous in living organisms. Their very high level of interspecies sequence homology underline the essential role hsps play as molecular chaperones in normal and pathological processes. As first observed in Drosophila, heat shock proteins are induced by a sudden increase in temperature (Ritossa, 1962). Since several of these proteins respond to a wider array of stressful conditions (oxidative damage, irradiation, metabolic toxins, starvation), hsps are also called stress proteins. Hsps are grouped into families according to their molecular weight. Hsp90s are the most abundant hsps and are expressed in a constitutive manner. Hsp90 binds to transcription factors which regulate the expression of hsps (Nadeau, Das, and Walsh, 1993) and has important roles in signal transduction, cell cycle regulation and development (Pratt and Toft, 1997; Rutherford and Lindquist, 1998). Hsp70s have transient peptide binding properties reversed by ATP (Bukau and Horwich, 1998). Under physiological conditions, Hsp70s assist folding and intracellular transport of newly synthesised polypeptides (Cyr and Neupert, 1996). Under stress conditions, induction of Hsp70 and subsequent binding, limits protein denaturation and aggregation (Hainaut and Milner, 1992; Yiping Yang et al., 1993). Similarly to the Hsp70s, the Hsp60 chaperonin family is crucial for protein folding, transport and oligomere subunit assembly (Hemmingsen et al., 1988; Agsteribbe et al., 1993; Bukau and Horwich, 1998). Bacterial members of the Hsp60 family, including the E coli GroEL and the mycobacterial hsp65, are highly conserved with over 90% amino acid Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib
Kluwer Academic/Plenum Publishers, New York, 2000.
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homology, and are amongst the most immunogenic molecules known (Kaufmann, 1990).
2. GENE THERAPY OF CANCER WITH HEAT SHOCK PROTEIN GENES
2.1. Transfer of Hsp65 Gene Protects Against J774 Histiocytic Sarcoma Studying the immune response to mycobacterial hsps, we serendipitously found that
hsp65 gene transfer has a profound anti-tumour effect (Lukacs et al., 1993). Transfection of J774 histiocytic sarcoma cells with the hsp65 gene resulted in a loss of tumorigenicity (Table 1) and immunisation of mice with hsp65-transfected sarcoma cells
protected them against a challenge with non-modified parent tumour cells. More importantly, treating mice with advanced tumours with hsp65 plasmid DNA complexed to liposomes resulted in tumour regression (Fig. 1). J774 reticulum sarcoma is a tumour vith aggressive in vivo g
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