Acyclic Nucleoside Phosphonates as Potential Antineoplastic Agents
Authors:
I. Votruba 1; B. Otová 2; A. Holý 1
Authors‘ workplace:
Ústav organické chemie a biochemie, v. v. i., AV ČR, Praha
1; Ústav biologie a lékařské genetiky 1. LF UK a VFN, Praha
2
Published in:
Čas. Lék. čes. 2008; 147: 471-477
Category:
Review Article
Overview
Recently, Gilead Sciences (Foster City, CA, USA) presented a potential cytostatic drug GS-9219. It is a novel lipophilic prodrug of cyprPMEDAP, in vivo releasing the active compound PMEG in a two-step process. GS-9219 has shown a substantial therapeutic potential in treatment of spontaneous non-Hodgkin’s lymphoma in dogs and its utilization in the human medicine is prospective. Hence, cyprPMEDAP represents a key intermediate in the intracellular activation of GS-9219. Both acyclic nucleoside phosphonates PMEG and cyprPMEDAP, serving as the basis for development of GS-9219, were discovered and their mechanism of action was investigated in detail at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. The biological studies using the rat lymphoma were carried out at the First Faculty of Medicine, Charles University.
Key words:
PMEG, GS-9219, non-Hodgkin lymphoma.
Sources
1. Holý, A.: Antiviral acyclic nucleotide analogues. In: Antibiotics and antiviral compounds (Krohn, K., Kirst, H., Maas, H., eds), Verlags-gesellschaft mbH, Weinheim, 1993, s. 455–462.
2. Snoeck, R., Van Cutsem, E., Van Ranst, M. et al.: (S)-1-(3--Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC): successful treatment of a patient with disseminated esophageal and hypo-pharyngeal papillomatosis. 5th International Skin Therapy Symposium, Brussels, Belgium, May 25–28, 1994, Abstract Book, 1994, s. 230.
3. Pavia, A. T., Meadows S., Tyring, S. K., Rallis, T. M.: Treatment of recalcitrant molluscum contagiosum with cidofovir. 5th Conf. Retrovir. Oppor. Infect. Abstract Book, 1998, s. 174.
4. Snoeck, R., Noel, J. C., Muller, C. et al.: Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia grade III (CIN III). J. Med. Virol., 2000, 60, s. 205–209.
5. Balzarini, J., Naesens, L., Herdewijn, P. et al.: Marked in vivo antiretrovirus activity of 9-(2-phosphonyl-methoxyethyl)adenine, a selective anti-human immunodefi-ciency virus agent. Proc. Natl. Acad. Sci. U.S.A., 1989, 86, s. 332–336.
6. Balzarini, J., Naesens, L., De Clercq, E.: Anti-retrovirus activity of 9-(2-phospho-nylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. Int. J. Cancer, 1990, 46, s. 337–340.
7. Balzarini, J., Sobis, H., Naesens, L. et al.: Inhibitory effects of 9-(2-phosphonylmethoxyethyl)adenine and 3’-azido-2’,3’-dideoxy-thymidine on tumor development in mice inoculated intracerebrally with Moloney murine sarcoma virus. Int. J. Cancer, 1990, 45, s. 486–489.
8. Balzarini, J., Hao, Z., Herdewijn, P. et al.: Intracellular metabolism and mechanism of antiretrovirus action of 9-(2--phosphonyl-methoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. Proc. Natl. Acad. Sci. U.S.A., 1991, 88, s. 1499-1503.
9. Balzarini, J., Naesens, L., Slachmuylders, J. et al.: 9-(2--phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS, 1991, 5, s. 21–28.
10. Balzarini, J.: Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharmacy World Sci., 1994, 16, s. 113–126.
11. De Clercq, E., Holý, A., Rosenberg, I. et al.: A novel selective broad-spectrum anti-DNA virus agent. Nature, 1986, 323, s. 464–467.
12. De Clercq, E., Sakuma, T., Baba, M. et al.: Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res., 1987, 8, s. 261–272.
13. De Clercq, E., Holý, A., Rosenberg, I.: Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob. Agents Chemother., 1989, 33, s. 185–191.
14. De Castro, L. M., Kern, E. R., De Clercq, E. et al.: Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS. Antiviral Res., 1991, 16, s. 101–114.
15. De Clercq, E.: Broad-spectrum anti-DNA virus and antiretrovirus activity of phosphonylmethoxyalkylpurine and – pyrimidines. Biochem. Pharmacol., 1991, 42, s. 963–972.
16. Yokota, T., Konno, K., Chonan, E. et al.: Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro. Antimicrob. Agents Chemother., 1990, 34, s. 1326–1330.
17. Yokota, T., Mochizuki, S., Konno, K. et al.: Phosphonylmethoxyalkyl derivatives of purine as inhibitors of human hepatitis B virus DNA synthesis. Nucleic Acids Symp. Ser., 1990, s. 17–18.
18. Yokota, T., Mochizuki, S., Konno, K. et al.: Phosphonylmethoxyalkyl derivatives of purine as inhibitors of human hepatitis B virus DNA synthesis. Nucleic Acids Symp. Ser., 1990, s. 17–18.
19. Holý, A., Rosenberg, I., Dvořáková, H.: Synthesis of N-(2--phosphonylmethoxy-ethyl) derivatives of heterocyclic bases. Collect. Czech. Chem. Commun., 1990, 54, s. 2190–2210.
20. Holý, A., Masojídková, M.: Synthesis of enantiomeric N-(2--phosphonomethoxy-propyl) derivatives of heterocyclic bases. I. Stepwise approach. Collect. Czech. Chem. Commun., 1995, 60, s. 1196–1212.
21. Balzarini, J., Holý, A., Jindřich, J., et al.: Differential antiherpes virus and antiretrovirus effects of the (S)- and (R)-enantiomers of acyclic nucleoside phosphonates. Potent and selective in vitro and in vivo antiretrovirus activity of the (R)-9-(2-phosphonomethoxypropyl) derivatives of heterocyclic bases. Antimicrob. Agents Chemother., 1993, 37, s. 332–338.
22. Balzarini, J., Aquaro, S., Perno, C. F., et al.: Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immuno-deficiency virus in different human cell systems. Biochem. Biophys. Res. Commun., 1996, 219, s. 337–341.
23. Ying, C., De Clercq, E., Neyts, J.: Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis B virus activity in cell culture. J. Viral Hepat., 2000, 7, s. 79–83.
24. Veselý, J., Merta, A., Votruba, I. et al.: The cytostatic effects and mechanism of action of antiviral acyclic adenine nucleotide analogs in L1210 mouse leukemia cells. Neoplasma, 1990, 37, s. 105–110.
25. Rose, W. C., Crosswell, A. R., Bronson, J. J., Martin, J. C.: In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]guanine and related phosphonate nucleotide analogues. J. Natl. Cancer. Inst., 1990, 82, s. 510–512.
26. Otová, B., Sladká, M., Votruba, I. et al.: Cytostatic effect of 9-(2-phosphonomethoxyethyl)adenine (PMEA). I. Lymphatic leukemia KHP-Lw-I in Lewis rats. Folia Biol. (Praha), 1993, 39, s. 136–141.
27. Otová, B., Sladká, M., Blažek, K. et al.: Cytostatic effect of 9-(2-phosphonomethoxyethyl)adenine (PMEA). II. Lymphoblastic leukemia in Sprague-Dawley rats. Folia Biol. (Praha), 1993, 39, s. 142–149.
28. Bílá, V., Otová, B., Jelínek, R. et al.: Antimitotic and teratogenic effects of acyclic nucleotide analogues 1-(S)-(3-hydroxy-2-phosphonomethoxyethyl)cytosine (HPMPC) and 9-(2-phosphonomethoxyethyl)adenine (PMEA). Folia Biol. (Praha), 1993, 39, s. 150–161.
29. Otová, B., Zídek, Z., Holý A. et al.: Immunomodulatory properties of 9-(2-phosphonomethoxyethyl)adenine (PMEA). Folia Biol. (Praha), 1994, 40, s. 185–192.
30. Calio, R., Villani, N., Balestra, E. et al.: Enhancement of natural killer activity and interferon induction by different acyclic nucleoside phosphonates. Antiviral Res., 1994, 23, s. 77–89.
31. Kunder, S. C., Black, P. L., Hall, B. E., Ussery, M. A.: PMEA has immuno-modulatory activity and inhibits reverse transcriptase in the Rauscher murine leukemia virus (RMuLV) model. Antiviral Res., 1995, 26, A276.
32. Zídek, Z., Franková, D., Holý A.: Stimulation of cytokine and nitric oxide production by acyclic nucleoside phosphonates. Nucleosides Nucleotides, 1991, 18, s. 959–961.
33. Zídek, Z., Franková, D., Holý, A.: Macrophage activation by antiviral acyclic nucleoside phosphonates in dependence on priming immune stimuli. Int. J. Immunopharmacol., 2000, 22, s. 1121–1129.
34. Zídek, Z., Franková, D., Holý, A.: Chemokines, nitric oxide and antiarthritic effects of 9-(2-phosphonomethoxyethyl)adenine (Adefovir). Eur. J. Pharmacol., 1999, 376, s. 91–100.
35. Otová, B., Křenová, D., Zídek, Z. et al.: Cytostatic effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA). III. Rat and mouse carcinomas and sarcomas. Folia Biol. (Praha), 1993, 39, s. 311–314.
36. Hatse, S., Naesens, L., Degreve, B. et al.: Potent antitumor activity of the acyclic nucleoside phosphonate 9-(2--phosphonylmethoxyethyl)adenine in choriocarcinoma-bearing rats. Int. J. Cancer, 1998, 76, s. 595–600.
37. Balzarini, J., Verstuyf, A., Hatse, S. et al.: The human immunodeficiency virus (HIV) inhibitor 9-(2-phosphonyl-methoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines. Int. J. Cancer, 1995, 61, s. 130–137.
38. Hatse, S., Naesens, L., De Clercq, E., Balzarini, J.: Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in the rat choriocarcinoma tumor cell model. Biochem. Pharmacol., 1998, 56, s. 851–859.
39. Otová, B., Sladká, M., Damoiseaux, J. et al.: Relevant Animal Model of Human Lymphoblastic Leukaemia/Lymphoma – Spontaneous T-Cell Lymphomas in an Inbred Sprague-Dawley Rat Strain (SD/Cub). Folia Biologica (Praha), 2002, 48, s. 213–226.
40. Holý, A., Zídek, Z., Votruba, I.: Inhibition of murine lymphocyte proliferation by N6-substituted acyclic purine nucleoside phosphonates. Collect. Czech. Chem. Commun., 1996, 61, s. S182–S187.
41. Hatse, S., Naesens, L., De Clercq, E., Balzarini, J.: N6‑Cyclopropyl-PMEDAP: A novel derivative of 9-(2--phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) with distinct metabolic, anti-proliferative and differentiation-inducing properties. Biochem. Pharmacol., 1999, 58, s. 311–323.
42. Valeriánová, M., Votruba, I., Holý, A. et al.: Antitumour activity of N6-substituted PMEDAP derivatives against T-cell lymphoma. Anticancer Res., 2001, 21, s. 2057–2064.
43. Otová, B., Holý, A., Votruba, I., et al.: Genotoxicity of Purine Acyclic Nucleotide Analogs. Folia Biol. (Praha), 1997, 43, s. 225–229.
44. Valerianova, M., Otova, B., Bila, V. et al.: PMEDAP and its N6-substituted derivatives: genotoxic effect and apoptosis in in vitro conditions. Anticancer Res. 2003, 23, s. 4933–4939.
45. Hatse, S., De Clercq, E. and Balzarini J.: Enhanced 9-(2--phosphonylmethoxy-ethyl)adenine secretion by a specific, indomethacine-sensitive efflux pump in a mutant 9-(2-phosphonylmethoxyethyl)adenine-resistant human erythroleukemia K562 cell line. Mol. Pharmacol. 1998, 54, s. 907–917.
46. Zápotocký, M., Hanzalová, J., Starková, J. et al.: Experimental therapy with PMEDAP – 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP): origin of resistance. Folia Biologica (Praha), 2007, 53, s. 79–84.
47. Otová, B., Francová, K., Franěk, F. et al.: 9-[2-(Phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP) – a potential drug against hematological malignancies – induces apoptosis. Anticancer Res., 1999, 19, s. 3173-3182.
48. Bobková, K., Otová, B., Marinov, I. et al.: Anticancer Effect of PMEDAP - Monitoring of Apoptosis. Anticancer Res., 2000, 20, s. 1041-1048.
49. Valeriánová, M., Votruba, I., Holý, A. et al.: N6-Substituted derivatives of PMEDAP: antitumor activity against T-cell lymphoma. Anticancer. Res., 2001, 21, s. 2057–2064.
50. Robins, B. L., Connelly, M. C., Marshall, D. et al.: A human T-lymphoid cell variant resistant to the acyclic nucleoside phosphonate, 9-(2-phosphonomethoxyethyl)adenine (PMEA), shows a unique combination of a phosphorylation effect and increased efflux of the agent. Mol. Pharmacol., 1995, 47, s. 391–397.
51. Krejčová, R., Horská, K., Votruba, I., Holý, A.: Phosphorylation of purine phosphonomethoxyalkyl derivatives by mitochondrial AMP kinase (AK2 type) from L1210 cells. Collect. Czech. Chem. Commun., 2000, 65, s. 1653–1668.
52. Krejčová, R., Horská, K., Votruba, I., Holý, A.: Isoenzymes of GMP kinase from L1210 cells: isolation and characterization. Collect. Czech. Chem. Commun., 1999, 64, s. 559–570.
53. Krejčová, R., Horská, K., Votruba, I., Holý, A.: Interaction of phosphono-methoxyalkyl derivatives of guanine with GMP kinase isoenzymes. Biochem. Pharmacol., 2000, 60, s. 1907–1913.
54. Šedivá, K., Ananiev, A. V., Votruba, I. et al.: Inhibition of purine nucleoside phosphorylase by phosphonylmethoxyalkyl analogues of nucleotides. Int. J. Pur. Pyr. Res., 1991, 2, s. 35–39.
55. Stockler, J. D.: Purine nucleoside phosphorylase: A target for chemotherapy. In Developments in Cancer Chemotherapy, CRC Press, Boca Raton, FL, 1984.
56. Sidi, Y., Mitchell, B. S.: 2’-Deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation. J. Clin. Invest., 1984, 74, s. 16480–16488.
57. Mattano, S. S., Palella, T. D., Mitchell, B. S.: Mutations induced at the hypoxanthine-guanine phosphoribosyltransferase locus of human T-lymphoblasts by perturbations of purine deoxyribonucleoside triphosphate pools. Cancer Res., 1990, 50, s. 4566–4571.
58. Lloyd, A. W.: Purine nucleoside phosphorylase inhibitors. Drug Discovery Today, 2000, 5, s. 85–86.
59. Horská, K., Votruba, I., Holý, A.: Interaction of phosphates of the acyclic nucleoside phosphonates with NDP kinase from yeast and bovine liver. Collect. Czech. Chem. Commun., 2006, 71, s. 35–43.
60. Kramata, P., Černý, J., Birkuš, G. et al.: DNA polymerases α, δ and ε from T-cell spontaneous lymphoblastic leukemia of Sprague-Dawley inbred rat: isolation and characterization. Collect. Czech. Chem. Commun., 1995, 60, s. 1555–1572.
61. Birkuš, G., Kramata, P., Votruba, I. et al.: Nonproteolyzed form of DNA polymerase from SD-lymphoma of Sprague-Dawley inbred rat: isolation and characterization. Collect. Czech. Chem. Commun., 1998, 63, s. 723–731.
62. Kramata, P., Votruba, I., Otová, B., Holý, A.: Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases α, δ, and ε. Mol. Pharmacol., 1996, 49, s. 1005–1011.
63. Birkuš, G., Votruba, I., Holý, A., Otová, B.: PMEApp as a substrate toward replicative DNA polymerases α, δ and ε*. Biochem. Pharmacol., 1999, 58, s. 487–492.
64. Kramata, P., Downey, K. M, Paborsky, L. R.: Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine (PMEG) by DNA polymerase delta and epsilon in vitro. J. Biol. Chem., 1998, 273, s. 21966–21971.
65. Hájek, M., Matulová, N., Votruba, I. et al.: Inhibition of human telomerase by diphosphates of acyclic nucleoside phosphonates. Biochem. Pharmacol., 2005, 70, s. 894–900.
66. Holý A., Votruba I., Tloušťová E. and Masojídková M.: Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, 2,6‑diaminopurines and related compounds. Collect. Czech. Chem. Commun., 2001, 66, s. 1545–1592.
67. Schinkmanová, M., Votruba, I., Holý, A.: N6-Methyl-AMP aminohydrolase activates N6-substituted purine acyclic nucleoside phosphonates. Biochem. Pharmacol., 2006, 71, s. 1370-1376.
68. Schinkmanová, M., Votruba, I., Shibata, R. et al.: Human N6-Methyl-AMP/dAMP aminohydrolase (abacavir 5’-monophosphate deaminase) is capable of metabolizing N6-substituted purine acyclic nucleoside phosphonates. Collect. Czech. Chem. Commun., 2007, 73, s. 275–291.
69. Reiser H., Ray A., Shibata R. et al.: GS-9219: A novel prodrug of 9-(2-phosphonomethoxyethyl)guanine (PMEG) with potent activity in hematologic malignancies. American Association for Cancer Research Annual Meeting, Los Angeles, 2007, abstr. 3188.
70. Vail D., Thamm D., Tumas D. et al: Efficacy and safety profile of GS-9219, a novel guanine nucleotide analog prodrug, for the treatment of lymphoid malignancies using pet dogs with spontaneous non-Hodgkin’s lymphoma as a model. American Association of Cancer Research Annual Meeting, Los Angeles, 2007, abstr. 5730.
Labels
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain managementArticle was published in
Journal of Czech Physicians
Most read in this issue
- Atherogenic Dyslipidemia and the Metabolic Syndrome: Pathophysiological Mechanisms
- Acute Abdomen in Elderly Patients
- Laparoscopic Surgery in Senior Age
- Acyclic Nucleoside Phosphonates as Potential Antineoplastic Agents