Abstract
This chapter describes an approach to destroying malignant cells by effectively changing the tumor phenotype through the delivery of Escherichia coli purine nucleo-side phosphorylase (PNP). In the presence of nucleoside prodrugs, this nonhuman enzyme in purine metabolism causes the death of the transfected (transduced) cells through the release of a highly potent antitumor agent. Importantly, the properties of the liberated compounds kill not only the transfected (transduced) cells but cause the efficient destruction of tumor cells that do not express the gene (i.e., bystander cells). In addition, the cytotoxic agents are active against both proliferating and nonproliferating tumor cells and, therefore, unlike other antitumor agents, this system can target the nonproliferating component of solid tumors. Many common cancers (including prostate, breast, colon, lung, brain, melanoma, pancreas, ovarian, kidney) progress to become untreatable and eventually cause death. Compounds are available that could abolish these tumors, but they are too toxic to systematically administer safely to cancer patients. We have shown that some of these compounds are remarkably potent and can abolish otherwise refractory human cancers when produced within the tumor mass by virtue of expression of E. coli PNP.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Mao, C., Cook, W. J., Zhou, M., Koszalka, G. W., Krenitsky, T. A., and Ealick, S. E. (1997) The crystal structure of Escherichia coli purine nucleoside phosphorylase: a comparison with the human enzyme reveals a conserved topology. Structure 5(10), 1373ā1383.
Ealick, S. E., Rule, S. A., Carter, D. C., et al. (1990) Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution. J. Biol. Chem. 265(3), 1812ā1820.
Zimmerman, T. P., Gersten, N., Ross, A. F., and Meich, R. P. (1971) Adenine as substrate for purine nucleoside phosphorlase. Can. J. Biochem. 49, 1050ā1054.
Jensen, K. F. and Nygaard, P. (1975) Purine nucleoside phosphorylase from Escherichia coli and Salmonella typhimurium. Purification and some properties. Eur. J. Biochem. 51, 253ā265.
Springer, C. J. and Niculescu-Duvaz, I. (2000) Prodrug-activating systems in suicide gene therapy. J. Clin. Invest. 105(9), 1161ā1167.
Sorscher, E. J., Peng, S., Bebok, Z., Allan, P. W., Bennett, L. L., Jr., and Parker, W. B. (1994) Tumor cell bystander killing in colonic carcinoma utilizing the E. coli Deo D gene and generation toxic purines. Gene Ther. 1, 233ā238.
Hughes, B. W., King, S. A., Allan, P. W., Parker, W. B., and Sorscher, E. J. (1998) Cell to cell contact is not required for bystander cell killing by E. coli purine nucleoside phosphorylase. J. Biol. Chem. 273, 2322ā2328.
Dionne, C. A., Camoratto, A. M., Jani, J. P., et al. (1998) Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin. Cancer Res. 4(8), 1887ā1898.
Sai, S., Takashi, M., Miyake, K., and Koshikawa, T. (1991) Study of growth fraction on fine needle aspirated prostatic tissue smear using monoclonal antibody Ki-67. Hinyokika KiyoāActa Urol. Japon. 37, 881ā886.
Sadi, M. V. and Barrack, E. R. (1991) Determination of growth fraction in advanced prostate cancer by Ki-67immunostaining and its relationship to the time to tumor progression after hormonal therapy. Cancer 67, 3065ā3071.
Tay, D. L., Bhathal, P. S., and Fox, R. M. (1991) Quantitation of G0 and G1 phase cells in primary carcinomas. Antibody to M1 subunit of ribonucleotide reductase shows F1 phase restriction point block. J. Clin. Invest. 87, 519ā527.
Giangaspero, F., Doglioni, C., Rivano, M. T., Pileri, S., Gerdes, J., and Stein, H. (1987) Growth fraction in human brain tumors defined by the monoclonal antibody Ki-67. Acta Neuropathol. 74, 179ā182.
Pierard, G. E. and Pierd-Franchimont, C. (1997) Stochastic relationship between the growth fraction and vascularity of thin malignant melanomas. Eur. J. Cancer 33, 1888ā1892.
Crafts, D. C., Hoshino, T., and Wilson, C. B. (1977) Current status of population kinetics in gliomas. Bull. Cancer 64, 115ā124.
Fontanini, G., Pingitore, R., Bigini, D., et al. (1992) Growth fraction in non-small cell lung cancer estimated by proliferating cell nuclear antigen and comparison with Ki-67 labeling and DNA flow cytometry data. Am. J. Pathol. 141, 1285ā1290.
Vescio, R. A., Connors, K. M., Bordin, G. M., et al. (1990) The distinction of small cell and non-small cell lung cancer by growth in native-state histoculture. Cancer Res. 50, 6095ā6099.
Parker, W. B., Allan, P. W., Shaddix, S. C., et al. (1998) Metabolism and metabolic actions of 6-methylpurine and 2-fluoroadenine in human cells. Biochem. Pharmacol. 55, 1673ā1681.
Gadi, V. K., Alexander, S. D., Waud, W. R., Alan, P., Parker, W. B., and Sorscher, E. J. (2002) A long acting suicide gene toxin, 6-methyl purine, inhibits slow growing tumors after a single administration. J. Pharmacol. Exp. Ther. 304, 1280ā1284.
Skipper, M. E., Montgomery, J. A., Tomson, J. R., and Schabel, F. M., Jr. (1959) Structure-activity relationship and cross resistance observed on a series of purine analogues against experimental neoplasm. Cancer Res. 19, 425ā437.
Philips, F. S., Sternberg, S. S, Hamilton, L., and Clarke, D. A. (1954) The toxic effects of 6-mercaptopurine and related compounds. Ann. NY Acad. Sci. 283.
Parker, W. B., King, S. A., Allan, P. W., et al. (1997) In vivo gene therapy of cancer with E. coli purine nucleoside phosphorylase. Hum. Gene Ther. 8, 1637ā1644.
Bass, B. L. (1992) The dsRNA unwinding/modifying activity: Fact and fiction. Semin. Dev. Biol. 3, 425ā433.
Clinical Gene Therapy Trial Data base. Available from http://www.wiley.com/wileychi/genmāÆer+Therapy&subcategory=.Ā®&start=40.
Sacco, M. G., Benedetti, S., Duflotdancer, A., et al. (1996) Partial regression, yet incomplete eradication of mammary tumors in transgenic mice by retrovirally mediated HSV-TK transfer in vivo. Gene Ther. 3, 1151ā1156.
Beck, C., Cayeux, S., Lupton, S. D., Dorken, B., and Blankenstein, T. (1995) The thymidine kinase/ganciclovir-mediated āsuicideā effect is variable in different tumor cells. Hum. Gene Ther. 6, 1525ā1530.
Dilber, M. S., Abedi, M. R., Christensson, B., et al. (1997) Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res. 57, 1523ā1528.
Elshami A. A., Saavedra, A., Zhang, H., et al. (1996) Gap junctions play a role in the ābystander effectā of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther. 3, 85ā92.
Fick, J., Barker, F. N., Dazin, P., Westphale, E. M., Beyer, E. C., and Israel, M. A. (1995) The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc. Natl. Acad. Sci. USA 92, 11,071ā11,075.
Imaizumi, K., Hasegawa, Y., Kawabe, T., et al. (1998) Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines. Am. J. Respir. Cell Mol. Biol. 18, 205ā212.
Freeman, S. M., Abboud, C. N., Whartenby, K. A., et al. (1993) The ābystander effectā: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 53, 5274ā5283.
Marini, III., F.C., Nelson J. A., and Lapeyre, J. N. (1995) Assessment of bystander effect potency produced by intratumoral implantation of HSVtk-expressing cells using surrogate marker secretion to monitor tumor growth kinetics. Gene Ther. 2, 655ā659.
Vile, R. G., Nelson, J. A., Castleden, S., Chong, H, and Hart, I. R. (1994) Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. Cancer Res. 54, 6228ā6234.
Caruso, M., Pham-Nguyen, K., Kwong, Y. L., et al. (1996) Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proc. Natl. Acad. Sci. USA 93, 11,302ā11,306.
Tapscott, S. J., Miller, A. D., Olson, J. M., Berger, M. S., Groudine, M., and Spence, A. M. (1994) Gene therapy of rat 9L gliosarcoma tumors by transduction with selectable genes does not require drug selection. Proc. Natl. Acad. Sci. USA 91, 8185ā8189.
Lockett, L. J., Molloy, P. L., Russell, P. J., and Both, G. W. (1997) Relative efficiency of tumor cell killing in vitro by two enzyme-prodrug systems delivered by identical adenovirus vectors. Clin. Cancer Res. 3, 2075ā2080.
DeVita, V. T., Hellman, S., and Rosenberg, S. A. (1997) Cancer: Principles & Practice of Oncology, 5th ed., Lippincott-Raven, Philadelphia, Vol. 2, p. 1176.
Moriuchi, S., Oligino, T., Krisky, D., et al. (1998) Enhanced tumor cell killing in the presence of ganciclovir by herpes simplex virus type 1 vector-directed coexpression of human tumor necrosis factor-alpha and herpes simplex virus thymidine kinase. Cancer Res. 58, 5731ā5737.
Freytag, S. O., Pogulski, K. R., Paielli, D. L., Gilbert, J. D., and Kim, J. H. (1998) A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum. Gene Ther. 9, 1323ā1333.
Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., and Debatin, K. M. (1999) Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc. Natl. Acad. Sci. USA 69, 8699ā8704.
Chen, S. H., Kosai, K., Xu, B., et al. (1996) Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. Cancer Res. 56, 3758ā3762.
Heise, C., Sampson-Johannes, A., Williams, A., McCormick, F., Von Hoff, D. D., and Kirn, D. H. (1997) ONYX-015, and E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med. 3, 639ā645.
Hughes, B. W., Wells, A. H., Bebok, Z., et al. (1995) Bystander killing of melanoma cells using the human tyrosinase promoter to express the Escherichia coli purine nucleoside phosphorylase gene. Cancer Res. 55, 3339ā3345.
Da Costa, L. T., Jen, J., Tong-Chuan, H., Chan, T. A., Kinzler, K. W., and Vogelstein, B. (1996) Converting cancer genes into killer genes. Proc. Natl. Acad. Sci. USA 93, 4192ā4196.
Nestler, U., Heinkelein, M., Lucke, M., et al. (1997) Foamy virus vectors for suicide gene therapy. Gene Ther. 4, 1270ā1277.
Martiniello-Wilks, R., Garcia-aragon, J., Daja, M. M., et al. (1998) In vivo gene therapy for prostate cancer: preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors. Hum. Gene Ther. 9, 1617ā1626.
Park, B. J., Brown, C. K., Hu, Y., et al. (1999) Augmentation of melanoma-specific gene expression using a tandem melanocyte-specific enhancer results in increased cytotoxicity of the purine nucleoside phosphorylase gene in melanoma. Hum. Gene Ther. 10, 889ā898.
Puhlmann, M., Gnant, M., Brown, C. K., Alexander, H. R., and Bartlett, D. L. (1999) Thymidine kinase-deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor-directed gene therapy. Hum. Gene Ther. 10, 649ā657.
Krohne, T. U., Shankara, S., Geissler, M., et al. (2001) Mechanisms of cell death induced by suicide genes encoding purine nucleoside phosphorylase and thymidine kinase in human hepatocellular carcinoma cells in vitro. Hepatology 34(3), 511ā518.
Mohr, L., Shankara, S., Yoon, S. K., et al. (2000) Gene therapy of hepatocellular carcinoma in vitro and in vivo in nude mice by adenoviral transfer of the Escherichia coli purine nucleoside phosphorylase gene. Hepatology 31(3), 606ā614.
Gadi, V. K., Alexander, S. D., Kudlow, J. E., Allan, P., Parker, W. B., and Sorscher, E. J. (2000) In vivo sensitization of ovarian tumors to chemotherapy by expression of E. coli purine nucleoside phosphorylase in a small fraction of tumor cells. Gene Ther. 7, 1738ā1743.
Secrist, J. A., Parker, W. B., Allan, P. W., et al. (1999) Gene therapy of cancer: activation of nucleoside prodrugs with E. coli purine nucleoside phosphorylase. Nucleosides Nucleotides 18, 745ā757.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
Ā© 2004 Humana Press Inc.
About this protocol
Cite this protocol
Curlee, K.V., Parker, W.B., Sorscher, E.J. (2004). Tumor Sensitization to Purine Analogs by E. coli PNP. In: Springer, C.J. (eds) Suicide Gene Therapy. Methods in Molecular Medicineā¢, vol 90. Humana Press. https://doi.org/10.1385/1-59259-429-8:223
Download citation
DOI: https://doi.org/10.1385/1-59259-429-8:223
Publisher Name: Humana Press
Print ISBN: 978-0-89603-971-1
Online ISBN: 978-1-59259-429-0
eBook Packages: Springer Protocols