Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies

References

• Nicander B, Reichard P. Dynamics of pyrimidine deoxynucleoside triphosphate pools in relationship to DNA synthesis in 3T6 mouse fibroblasts. Proc. Natl Acad. Sci. USA 80(5), 1347–1351 (1983).
   Google Scholar
• Mathews CK, Ji J. DNA precursor asymmetries, replication fidelity, and variable genome evolution. Bioessays 14(5), 295–301 (1992).
   PubMed Web of Science ®Google Scholar
• Reddy GP, Pager RS. Replitase: a complex integrating dNTP synthesis and DNA replication. Grit. Rev. Eukaryot. Gene Expr. 3(4), 255–277 (1993).
   Google Scholar
• Reichard P, Ehrenberg A. Ribonucleotide reductase — a radical enzyme. Science 221(4610), 514–519 (1983).
   PubMed Web of Science ®Google Scholar
• Reichard P. From RNA to DNA, why so many ribonucleotide reductases? Science 260(5115), 1773–1777 (1993).
   Google Scholar
• Fontecave M, Nordlund P, Eldund H, Reichard P The redox centers of ribonucleotide reductase of Escherichia coil. Adv. Enzymol Relat. Areas Mal Biol. 65 147–183 (1992).
   PubMedGoogle Scholar
• Nordlund P, Eklund H. Structure and function of the Escherichia cob ribonucleotide reductase protein R2. Mal Biol. 232(1), 123–164 (1993).
   Google Scholar
• Nyholm S, Mann GJ, Johansson AG, Bergeron RJ, Graslund A, Thelander L. Role of ribonucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J. Biol. Chem. 268(35), 26200–26205 (1993).
   Google Scholar
• Sahlin M, Sjoberg BM, Loehr T, Sanders-Loehr J. Activation of the iron-containing B2 protein of ribonucleotide reductase by hydrogen peroxide. Biochem. Biophys. Res. Commun. 167(2), 813–818 (1990). toEliasson R, Pontis E, Jordan A, Reichard P. Allosteric regulation of the third ribonucleotide reductase (NrdEF enzyme) from enterobacteriaceae. j Biol. Chem. 271(43), 26582–26587 (1996).
   Google Scholar
• Thelander L, Reichard P. Reduction of ribonucleotides. Ann. Rev Biochem. 48, 133–158 (1979).
   PubMed Web of Science ®Google Scholar
• Cory JG, Sato A. Regulation of ribonucleotide reductase activity in mammalian cells. Mal Cell Biochem. 53-54(1–2), 257–266 (1983).
   Google Scholar
• Elford HL, Freese M, Passamani E, Morris HP Ribonucleotide reductase and cell proliferation. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. j Biol. Chem. 245(20), 5228–5233 (1970).
   Google Scholar
• Takeda E, Weber G. Role of ribonucleotide reductase in expression in the neoplastic program. Life Sci. 28 (9), 1007–1014 (1981).
   Google Scholar
• Elford HL. Functional regulation of mammalian ribonucleotide reductase. Adv. Enzyme Regul 10,19–38 (1972).
   PubMedGoogle Scholar
• Weber G. Enzymology of cancer cells. N Engif Med. 296(10), 541–551 (1977).
   Google Scholar
• Weber G. Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Memorial Lecture. Cancer Res. 43(8), 3466–3492 (1983).
   Google Scholar
• Duan J, Liuzzi M, Paris Wet al. Antiviral activity of a selective ribonucleotide reductase inhibitor against acyclovir-resistant herpes simplex virus type 1 in vivo. Antimicrob. Agents Chemother. 42(7), 1629–1635 (1998).
   Google Scholar
• Reardon JE, Spector T Acyclovir: mechanism of antiviral action and potentiation by ribonucleotide reductase inhibitors. Adv Pharmacol 22,1–27 (1991).
   PubMedGoogle Scholar
• Lien EJ. Ribonucleotide reductase inhibitors as anticancer and antiviral agents. Prog. Drug Res. 31,101–126 (1987).
   PubMedGoogle Scholar
• Cory JG, Carter GL. Drug action on ribonucleotide reductase. Adv. Enzyme Regul 24,385–401 (1985).
   PubMedGoogle Scholar
• Cory JG. Ribonucleotide reductase as a chemotherapeutic target. Adv. Enzyme Regul 27,437–545 (1988).
   PubMedGoogle Scholar
• Cory JG, Carter GL. Leukemia L1210 cell lines resistant to ribonucleotide reductase inhibitors. Cancer Res. 48(4), 839–843 (1988).
   Google Scholar
• Li J, Zheng LM, King I, Doyle TW, Chen SH. Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. Curr. Med. Chem. 8(2), 121–133 (2001).
   Google Scholar
• •This study demonstrates that 3-AP prodrugs have improved pharmaceutical, biological and toxicity profiles in comparison with 3–AP
   Google Scholar
• Thelander L, Graslund A. Mechanism of inhibition of mammalian ribonucleotide reductase by the iron chelate of 1-formylisoquinoline thiosemicarbazone. Destruction of the tyrosine free radical of the enzyme in an oxygen-requiring reaction. j Biol. Chem. 258(7), 4063–4066 (1983).
   Google Scholar
• Carter GL, Cory JG. Cross-resistance patterns in hydroxyurea-resistant leukemia L1210 cells. Cancer Res. 48(20), 5796–5799 (1988).
   Google Scholar
• Wright JA, Chan AK, Choy BK, Hurta AR, McClarty GA, Tagger AY. Regulation and drug resistance mechanisms of mammalian ribonucleotide reductase, and the significance to DNA synthesis. Biochem. Cell Biol. 68(12), 1364–1371 (1990).
   PubMed Web of Science ®Google Scholar
• Nicander B, Reichard P. Relations between synthesis of deoxyribonucleotides and DNA replication in 3T6 fibroblasts. Chem. 260(9), 5376–5381 (1985).
   Google Scholar
• Wadler S, Horowitz R, Rao J, Mao X, Schlesinger K, Schwartz EL. Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: effects in wild-type and resistant human colon cancer cells. Cancer Chemother. Pharmacol 38(6), 522–528 (1996).
   Google Scholar
• Becldoff GL, Lerner HJ, Frost D, Russo-Alesi FM, Gitomer S. Hydroxyurea (NSC-32065) in biologic fluids: dose-concentration relationship. Cancer Chemother Rep. 48,57-58 (1965).
   Google Scholar
• Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin. Pharmacokinet. 34(5), 347–358 (1998).
   PubMed Web of Science ®Google Scholar
• Moore EC, Hurlbert RB. The Inhibition of ribonucleoside diphosphate reductase by hydroxyurea, guanazole and pyrazoloimidazole (IMPY). In: Inhibitors of Ribonucleoside Diphosphate Reductase Activity Cory JGaC, AH (Ed), Pergamon Press, Oxford, UK, 165–201 (1989).
   Google Scholar
• Donehower RC: Hydroxyurea. In: Cancer Chemotherapy and Biotherapy. Chabner BAL, CL (Ed), Lippincott-Raver, Philadelphia, PA, USA, 253–260 (1996).
   Google Scholar
• Wright JA. Altered mammalian ribonucleoside diphosphate reductase from mutant cell lines. In: Inhibitors of Ribonucleotide Diphosphate Reductase Activity Gory JGG, (Ed.), Pergamon Press, New York, NY, USA 89–111 (1989).
   Google Scholar
• Bianchi V, Pontis E, Reichard P. Changes of deoxyribonucleoside triphosphatte pools induced by hydroxyurea and their relation to DNA synthesis. J. Biol. Chem. 261(34), 16037–16042 (1986).
   Google Scholar
• Rushing D, Goldman A, Gibbs G, Howe R, Kennedy BJ. Hydroxyurea versus busulfan in the treatment of chronic muyelogenous leukemia. Am. j Clin. Oncol 5(3), 307–313 (1982).
   Google Scholar
• Bolin RVV, Robinson WA, Sutherland J, Hamman RE Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. Cancer 50(9), 1683–1686 (1982).
   PubMed Web of Science ®Google Scholar
• Hehlmann R, Heimpel H, Hasford J al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. B/ooc/82 (2), 398–407 (1993).
   Google Scholar
• Interferon-a versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. Natl Cancer Inst. 89(21), 1616–1620 (1997).
   Google Scholar
• Silver RT, Woolf SH, Hehlmann R et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood 94(5), 1517–1536 (1999).
   PubMed Web of Science ®Google Scholar
• Keating MJ, Kantarjian H, O'Brien S et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J. Clin. Oncol 9(1), 44–49 (1991). This study demonstrated that fludarabine is the most cytoreductive single-agent in CLL.
   Google Scholar
• Keating MJ, O'Brien S, Kantarjian H et al. Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. B/ooc/81(11), 2878–2884 (1993).
   Google Scholar
• Johnson S, Smith AG, Loffler H et al Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 347(9013), 1432–1438 (1996).
   PubMed Web of Science ®Google Scholar
• Keating MJ, O'Brien S, Lerner S et al Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. B/ooc/92 (4), 1165–1171 (1998).
   Google Scholar
• Rai KR, Peterson BL, Appelbaum FR et al Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N big/ J. Med. 343(24), 1750–1757 (2000). This randomized comparison of fludarabine with chlorambucil demonstrated that fludarabine yields higher response rates, longer remission durations and longer progression-free survival than chlorambucil.
   Google Scholar
• Leporrier M, Chevret S, Cazin B al. Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated patients Stage B and C chronic lymphocytic leukemia patients. Blood 98(8), 2319–2325 (2001).
   Google Scholar
• O'Brien SM, Kantarjian HM, Cortes J et al Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J. Clin. Oncol 19(5), 1414–1420 (2001).
   Google Scholar
• O'Brien S, Kantarjian H, Beran M et al Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82(6), 1695–1700 (1993).
   Google Scholar
• Wierda W, O'Brien S, Albitar M et al. Combined fludarabine, cyclophosphamide, and rituximab achieves a high complete remission rate as initial treatment for chronic lymphocytic leukemia. Blood 98(11), 771a (2001).
   PubMed Web of Science ®Google Scholar
• Solal-Celigny P, Brice P, Brousse N et al. Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d'Etude des Lymphomes de l'Adulte. I Clin. Oncol 14(2), 514–519 (1996).
   Google Scholar
• McLaughlin P, Hagemeister FB, Swan F et al. Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. Clin. °rico]. 12(3), 575–579 (1994).
   PubMed Web of Science ®Google Scholar
• McLaughlin P, Hagemeister FB, Romaguera JE et al Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. Clin. Oncol 14(4), 1262–1268 (1996).
   Web of Science ®Google Scholar
• Tsimberidou AM, McLaughlin P, Younes A et al. Randomized compariston of fludarabine-novantrone-dexamethasone (FND) versusCHOD-Bleo/ESHAP/NOPP (alternating triple therapy; Arl ) in patients with Stage IV indolent lymphoma. Blood 96(11), 508a (2000).
   Web of Science ®Google Scholar
• Emmanouilides C, Rosen P, Rasti S, Territo M, Kunkel L. Treatment of indolent lymphoma with fludarabine/ mitoxantrone combination: a Phase II trial. Hematol Oncol 16 (3), 107–116 (1998).
   PubMed Web of Science ®Google Scholar
• Crawley CR, Foran JM, Gupta RK et al. A Phase II study to evaluate the combination of fludarabine, mitoxantrone, and dexamethasone (FMD) in patients with follicular lymphoma. Ann. Oncol 11(7), 861–865 (2000).
   PubMed Web of Science ®Google Scholar
• Foussard C, Deconninck E, Desablens B et al. Improved response after fludarabine, mitoxantrone (FM) in first line treatment of patients with advanced low-grade non-Hodgkin's lymhoma (LG-LNH). Proc. Ann. Soc. Clin. Oncol 20 (2001).
   Google Scholar
• Zinzani PL. A randomized trial of fludarabine and mitoxantrone plus rituximab versus CHOP plus rituximab as first-line treatment in patetns with follicular lymphoma. B/ooc/98 (11), 842a (2001).
   Google Scholar
• Velasquez W Lew D, Miller T, Fisher R. SWOG 95–01: a Phase II trial of a combination of fludarabine and mitoxantrone (FN) in untreated advanced low grade lymphoma. An effective, well tolerated regimen. Proc. Ann. Soc. Clin. Oncol 9a (1999).
   Google Scholar
• Hochster HS, Oken MM, Winter JN et al. Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up--a report from the Eastern Cooperative Oncology Group. Clin. Oiled 18(5), 987–994 (2000).
   PubMed Web of Science ®Google Scholar
• Gandhi V, Estey E, Keating MJ, Plunkett W Biochemical modulation of arabinosylcytosine for therapy of leukemias. Leuk. LymphomalO(Suppl.), 109–114 (1993).
   Google Scholar
• Gandhi V, Estey E, Keating MJ, Plunkett W Fludarabine potentiates metabolism of arabinosyl cytosine in patients with acute myelogenous leukemia during therapy. Clin. Oncol 11(1), 116–124 (1993).
   Web of Science ®Google Scholar
• Estey E, Plunkett W, Gandhi V, Rios MB, Kantarjian H, Keating MJ. Fludarabine and arabinosylcytosine therapy for refractory and relapsed acute myelogenous leukemia. Leuk. Lymphoma 9(4-5), 343–350 (1993).
   PubMed Web of Science ®Google Scholar
• Estey E, Thall P, Andreeff M et al. Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J. Clin. Oncol. 12(4), 671–678 (1994).
   Google Scholar
• Parker JE, Pagliuca A, Mijovic A et al Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. BE j kkematol 99(4), 939–944 (1997).
   PubMed Web of Science ®Google Scholar
• Fleischhack G, Hasan C, Graf N, Mann G, Bode U. IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a Phase II trial. Br. kkematol. 102(3), 647–655 (1998).
   Google Scholar
• Estey EH, Thall PF, Cortes JE et al Comparison of idarubicin + am-C-, fludarabine + am-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. B/ooc/98(13), 3575–3583 (2001).
   Google Scholar
• ••Fludarabine-based combinations areinferior to idarubicin plus ara-C in the treatment of most patients with AML, RAEB or RAEB-T.
   Google Scholar
• Lauria F, Rondelli D, Zinzani P et al Long-lasting complete remission in patients with hairy cell leukemia treated with 2-CdA: a 5-year survey. Leukemia 11(5), 629–632 (1997). This study documents striking activity of cladribine in HCL.
   Google Scholar
• Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl. I Med. 322(16), 1117–1121 (1990).
   Google Scholar
• Dearden CE, Matutes E, Hilditch BL, Swansbury GJ, Catovsky D. Long-term follow-up of patients with hairy cell leukaemia after treatment with pentostatin or cladribine. Br. kkematol 106(2), 515–519 (1999).
   Google Scholar
• Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. B/ooc/ 92 (6), 1918–1926 (1998).
   Google Scholar
• Cheson BD, Sorensen JM, Vena DA et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. Clin. Oncol 16(9), 3007–3015 (1998).
   Google Scholar
• ••This report confirms the excellent response rates and remission durations associated with cladribine therapy in patients with HCL.
   Google Scholar
• Tallman MS, Hakimian D, Kopecky KJ et al Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2'-deoxycoformycin and prediction of early relapse. Clin. Cancer Res. 5(7), 1665–1670 (1999).
   Google Scholar
• Seymour JF, Kurzrock R, Freireich EJ, Estey EH. 2-chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia. Blood 83(10), 2906–2911 (1994).
   Google Scholar
• Tallman MS, Hakimian D, Rademaker AW et al Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University Experience. B/ooc/88 (6), 1954-1959 (1996).
   Google Scholar
• Hoffman MA, Janson D, Rose E, Rai KR. Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up.j Clin. Oncol 15(3), 1138–1142 (1997).
   Google Scholar
• Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. j Clin. Oncol 17(8), 2454–2460 (1999).
   Google Scholar
• Piro LD, Carrera CJ, Beutler E, Carson DA. 2-Chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukemia. Blooc172(3), 1069–1073 (1988).
   Google Scholar
• Saven A, Lemon RII, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. j Clin. Oncol 13(3), 570–574 (1995).
   Google Scholar
• Robak T, Blasinska-Morawiec M, Blonski JZ, Dmoszynska A. 2-Chlorodeoxyadenosine (cladribine) in the treatment of elderly patients with B-cell chronic lymphocytic leukemia. Leuk. Lymphoma 34(1–2), 151–157 (1999).
   Google Scholar
• Robak T, Blonski JZ, Urbanska-Rys H, Blasinska-Morawiec M, Skotnicki AB. 2-Chlorodeoxyadenosine (Cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old or younger. Leukemia 13(4), 518–523 (1999).
   Google Scholar
• Betticher DC, Ratschiller D, Hsu Schmitz SF et al Reduced dose of subcutaneous cladribine induces identical response rates but decreased toxicity in pretreated chronic lymphocytic leukaemia. Swiss Group for Clinical Cancer Research. Ann. Oncol 9(7), 721–726 (1998).
   Google Scholar
• Robak T, Blonski JZ, Kasznicki M et al Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 96 (8), 2723–2729 (2000).
   PubMed Web of Science ®Google Scholar
• Robak T, Blonski JZ, Kasznicki M et al Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukemia — updated results of the multicentre study of 378 patients. BE kkematol 108(2), 357–368 (2000).
   Google Scholar
• Tefferi A, Witzig TE, Reid JM, Li CY, Ames MM. Phase I study of combined 2-chlorodeoxyadenosine and chlorambucil in chronic lymphoid leukemia and low-grade lymphoma. j Clin. Oncol 12(3), 569–574 (1994).
   Google Scholar
• Tefferi A, Levitt R, Li CY et al Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously untreated B-cell chronic lymphocytic leukemia. Am. j Clin. Oncol 22(5), 509–516 (1999).
   Google Scholar
• Robak T, Blonski JZ, Kasznicki M et al. Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia. Leukemia 15 (10), 1510–1516 (2001).
   PubMed Web of Science ®Google Scholar
• Robak T, Gora-Tybor J, Lech-Maranda E, Blonski JZ, Kasznicki M. Cladribine in combination with mitoxantrone and cyclophosphamide (CMC) in the treatment of heavily pre-treated patients with advanced indolent lymphoid malignancies. Eur. I Haematol. 66(3), 188–194 (2001).
   PubMed Web of Science ®Google Scholar
• Tallman MS, Hakimian D, Zanzig C et al. Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia. Clin. Oncol 13(4), 983–988 (1995).
   Web of Science ®Google Scholar
• Juliusson G, Liliemark J. Long term survival previously following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia. Ann. Oncol 7(4), 373–379 (1996).
   Google Scholar
• Juliusson G, Christiansen I, Hansen MM et al Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia. Clin. Oncol 14 (7), 2160–2166 (1996).
   Web of Science ®Google Scholar
• Huang P, Plunkett W Induction of apoptosis by gemcitabine. Semin. Oiled 22(4 Supp1.11), 19–25 (1995).
   Google Scholar
• van der Donk WA, Yu G, Silva DJ et al Inactivation of ribonucleotide reductase by (E)-2'-fluoromethylene-2'-deoxycytidine 5'-diphosphate: a paradigm for nucleotide mechanism-based inhibitors. Biochemistry 35(25), 8381–8391 (1996).
   Google Scholar
• Baker CH, Banzon J, Bollinger JM et al. 2'- deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase. j Med. Chem. 34(6), 1879–1884 (1991).
   Google Scholar
• Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin. Oncol 22(4 Supp1.11), 3–10 (1995).
   Google Scholar
• •Excellent review on gemcitabine and its mechanisms of action.
   Google Scholar
• Manegold C, Zatloukal P, Krejcy K, Blotter J. Gemcitabine in non-small cell lung cancer (NSCLC). Invest. New Drugs 18 (1), 29–42 (2000).
   PubMed Web of Science ®Google Scholar
• Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R. An investigational new drug treatment program for patients with gemcitabine: results for over 3,000 patients with pancreatic carcinoma. Cancer 85 (6), 1261–1268 (1999).
   Google Scholar
• Carmichael J, Possinger K, Phillip P et al Advanced breast cancer: a Phase II trial with gemcitabine. j Clin. Oncol 13(11), 2731–2736 (1995).
   Google Scholar
• Lund B, Hansen OP, Theilade K, Hansen M, Neijt JR Phase II study of gemcitabine (2, 2'difluorodeoxycytidine) in previously treated ovarian cancer patients. j Nall Cancer Inst. 86 (20), 1530–1533 (1994).
   Google Scholar
• Catimel G, Vermorken JB, Clavel M et al. A Phase II study of gemcitabine (LY188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC early clinical trials group. Ann. Oncol 5(6), 543–547 (1994). too Peters GJ, Ruiz van Haperen VW, Bergman AM et al Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin. Oncol 23(5 Supp1.10), 16–24 (1996).
   Google Scholar
• Abratt RP, Bezwoda WR, Goedhals L, Hacking DJ. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small cell lung cancer. Clin. °rico]. 15(2), 744–749 (1997).
   PubMed Web of Science ®Google Scholar
• Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small cell lung cancer: a Phase II study. j Clin. Oncol 15(1), 297–303 (1997).
   Google Scholar
• Haider K, Kornek GV, Kwasny W et al Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor. Breast Cancer Res. Brat. 55(3), 203–211 (1999).
   Google Scholar
• Csoka K, Liliemark J, Larsson R, Nygren P. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin. Oncol 22(4 Supp1.11), 47–53 (1995).
   Google Scholar
• Bouffard DY, Momparler LF, Momparler RL. Comparison of antineoplastic activity of 2',2'-difluorodeoxycytidine and cytosine arabinoside against human myeloid and lymphoid leukemic cells. Anticancer Drugs 2(1), 49–55 (1991).
   Google Scholar
• Bernell P, Ohm L. Promising activity of gemcitabine in refractory high-grade non-Hodgkin's lymphoma. BE j Haematol 101(1), 203–204 (1998).
   PubMed Web of Science ®Google Scholar
• Zinzani PL, Magagnoli M, Bendandi M et al. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann. Oncol 9 (12), 1351–1353 (1998).
   PubMed Web of Science ®Google Scholar
• Fossa A, Santoro A, Hiddemann W et al. Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. Clin. Oiled 17(12), 3786–3792 (1999).
   PubMed Web of Science ®Google Scholar
• Savage DG, Rule SA, Tighe M et al Gemcitabine for relapsed or resistant lymphoma. Ann. Oncol 11(5), 595–597 (2000).
   PubMed Web of Science ®Google Scholar
• Rizzieri D, Gockerman J, Decastro C. Phase I trial of continuously infused gemcitabine with CPT-11 for refractory hematologic malignancies. Blooc196, 216b (2000). in Santoro A, Bredenfeld H, Devizzi L et al Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter Phase II study." Clin. Oiled 18(13), 2615–2619 (2000).
   Google Scholar
• Sezer O, Eucker J, Jakob C, Kaufmann O, Schmid P, Possinger K. Achievement of complete remission in refractory Hodgkin's disease with prolonged infusion of gemcitabine. Invest. New Drugs19(1), 101–104 (2001).
   PubMed Web of Science ®Google Scholar
• Grunewald R, Kantarjian H, Du M, Faucher K, Tarassoff P, Plunkett W Gemcitabine in leukemia: a Phase I clinical, plasma, and pharmacology study. j Clin. Oncol 10(3), 406–413 (1992).
   Google Scholar
• Rizzieri D, Bass AJ, Rosner GL et al. Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia. j Clin. Oiled 20(3), 674–679 (2002).
   Google Scholar
• Gandhi V, Plunkett W, Du M, Ayres M, Estey EH. Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a Phase I trial in relapsed acute myelogenous leukemia. j Clin. Oncol 20(3), 665–673 (2002).
   Google Scholar
• Tosi P, Pellacani A, Zinzani PL, Magagnoli M, Visani G, Tura S. In vitm study of the combination gemcitabine + fludarabine on freshly isolated chronic lymphocytic leukemia cells. Hematologica 84(9), 794–798 (1999).
   PubMed Web of Science ®Google Scholar
• Schirmer M, Geisen F, Tiefenthaler M, Konwalinka G. Differential effects of cladribine and gemcitabine on erythroid and granulocytic progenitors from patients with chronic myeloid leukemia. Leuk. Res. 23(12), 1121–1126 (1999).
   PubMed Web of Science ®Google Scholar
• Lech-Maranda E, Korycka A, Robak T. The interaction of gemcitabine and cytarabine on murine leukemias L1210 or P388 and on human normal and leukemic cell growth in vitro. Haematologica 85 (6), 588–594 (2000).
   Google Scholar
• Gruber J, Geisen F, Sgonc R et al 2',2'-Difluorodeoxycytidine (gemcitabine) induces apoptosis in myeloma cell lines resistant to steroids and 2-chlorodeoxyadenosine (2-CdA). Stem Celis 14(3), 351–362 (1996).
   Google Scholar
• Gazitt Y, Roodman D, Freytes C. A Phase I—II clinical trial with a combination of gemcitabine and paclitaxel for the treatment of refractory multiple myeloma. Blood 96,287b (2000).
   Google Scholar
• Offidani M, Mele A, Marconi M. Gemcitabine or gemcitabine-cisplatin in advanced multiple myeloma: an going study. Blood96, 291b (2000).
   Web of Science ®Google Scholar
• Lyamu WE, Adunyah SE, Fasold H et al Enhancement of hemoglobin and F-cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (didox and trimidox) in combination with streptozotocin. ArnHernatol 63(4), 176–183 (2000).
   Google Scholar
• Szekeres T, Vielnascher E, Novotny L et al. Iron binding capacity of trimidox (3,4,5-trihydroxybenzamidoxime), a new inhibitor of the enzyme ribonucleotide reductase. Eur j Gun. Chem. Gun. Biochem. 33(11), 785–789 (1995).
   Google Scholar
• Szekeres T, Gharehbaghi K, Fritzer M et al. Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase. Cancer Chemother. Pharmacol 34(1), 63–66 (1994).
   Web of Science ®Google Scholar
• Szekeres T, Fritzer M, Strobl H et al Synergistic growth inhibition and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. Blood 84(12), 4316–4321 (1994).
   Google Scholar
• Fritzer-Szekeres M, Grusch M, Luxbacher C et al Trimidox, an inhibitor of ribonucleotide reductase, induces apoptosis and activates caspases in HL-60 promyelocytic leukemia cells. Exp. Remota'. 28(8), 924–930 (2000).
   Google Scholar
• Lee R, Beauparlant P, Efford H, Ponka P, Hiscott J. Selective inhibition oflicB-a phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds. Vimlogy234(2), 277–290 (1997).
   Google Scholar
• Kimura S, Maekawa T, Hirakawa K, Murakami A, Abe T Alterations of c-myc expression by antisense oligonudeotides enhance the induction of apoptoisis in HL-60 cells. Cancer Res. 55(6), 1379–1384 (1995).
   Google Scholar
• Fritzer-Szekeres M, Novotny L, Romanova D et al Enhanced effects of adriamycin by combination with a new ribonucleotide reductase inhibitor, trimidox, in murine leukemia. Life Sci. 63(7), 545–552 (1998).
   Google Scholar
• Investigator's brochures. Matrix Pharmaceuticals, Inc. (2000).
   Google Scholar
• Zhou Y, Achanta G, Pelicano H, Gandhi V, Plunkett W Huang P. Action of (E)-2'-deoxy-2'-(fluoromethylene)cytidine on DNA metabolism: incorporation, excision, and cellular response. Mal Pharmacol 61(1), 222–229 (2002).
   Google Scholar
• Skierski JS, Koronkiewicz M, Grieb P. Effect of FMdC on the cell cycle of some leukemia cell lines. Cytometry37 (4), 302–307 (1999).
   PubMedGoogle Scholar
• Snyder RD. Effect of 2'-deoxy-2'-(fluoromethylene) cytidine on the ultraviolet and X-ray sensitivity of HeLa cells. Oncology Res. 6(4–5), 177–182 (1994).
   Google Scholar
• Coucke PA, Decosterd LA, Li YX et al. The ribonucleoside diphosphate reductase inhibitor (E)-2'-deoxy-(fluoromethylene)cytidine as a cytotoxic radiosensitizer in vitro. Cancer Res. 59(20), 5219–5226 (1999).
   Google Scholar
• Sun LQ, Li YX, Guillou L, Coucke PA. (E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts. Cancer Res. 58(23), 5411–5417 (1998).
   Google Scholar
• Masuda N, Negoro S, Takeda K et al. Phase land pharmacologic study of oral (E)-2'-deoxy-2'-(fluoromethylene) cytidine: on a daily x 5-day schedule. Invest. New Drugs 16(3), 245–254 (1998–1999).
   Google Scholar
• Faderl S, Thomas DA, Cortes J et al Phase I study of tezacitabine, an antimetabolite deoxycytidine analog, in patients with relapsed and refractory hematologic malignancies. Blood 96(11), 724a (2000).
   Web of Science ®Google Scholar
• Seley KL. Tezacitabine Hoechst Marion Roussel. Curl: Opin. Investig. Drugs1(1), 135–140 (2000).
   Google Scholar
• Liu MC, Lin TS, Sartorelli AC. Synthesis and antitumor activity of aminoderivatives of pyridine-2-carboxaldehyde thiosemicarbazone. j Med. Chem. 35 (20), 3672–3677 (1992).
   Google Scholar
• Liu MC, Lin TS, Penketh P, Sartorelli AC. Synthesis and antitumor activity of 4- and 5-substituted derivatives of isoquinoline-l-carboxaldehyde thiosemicarbazone. j Med. Chem. 38(21), 4234–4243 (1995).
   Google Scholar
• DeConti RC, Toftness BR, Agrawal KC et al Clinical and pharmacological studies with 5-hydroxy-2-formylpyridine thiosemicarbazone. Cancer Res. 32 (7), 1455–1462 (1972).
   Google Scholar
• Krakoff IH, Etcubanas E, Tan C, Mayer K, Bethune V, Burchenal JH. Clinical trial of 5-hydroxypicolinaldehyde thiosemicarbazone (5—HP; NSC-107392), with special reference to its iron-chelating properties. Cancer Chemother. Rep. 58(2), 207–212 (1974).
   Google Scholar
• Wang Y, Liu MC, Lin TS, Sartorelli AC. Synthesis and antitumor activity of 3- and 5-hydroxy-4-methylpyridine-2-carboxaldehyde thiosemicarbazones. Med. Chem. 35(20), 3667–3671 (1992).
   Google Scholar
• Cory JG, Cory AH, Rappa G et al Inhibitors of ribonucleotide reductase: comparative effects of amino- and hydroxy-substituted pyrimdine-2-carboxaldehyde thiosemicarbazones. Biochem. Pharmacol 48(2), 335–344 (1994).
   Google Scholar
• Cory JG, Cory AH, Rappa G et al Structure-function relationships for a new series of pyridine-2-carboxaldehyde thiosemicarbazones on ribonucleotide reductase activity and tumor cell growth in culture and in vivo. Adv. Enzyme Reg. 35, 55–68 (1995).
   Google Scholar
• Finch RA, Liu M, Grill SP et al Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Phatmacol 59(8), 983–991 (2000).
   Google Scholar
• Liu MC, Lin TS, Cory JG, Cory AH, Sartorelli AC. Synthesis and biological activity of 3- and 5- amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. j Med. Chem. 39 (13), 2586–2593 (1996).
   Google Scholar
• GaoWY,CaraA,GalloRC,LoriE Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1replication. Floc. Natl Acad. Li. USA 90(19), 8925–8928 (1993).
   Google Scholar
• Lori F, Malykh A, Cara A et al Hydroxyurea as an inhibitor of human immunodeficiency virus — Type 1 replication. Science 266 (5186), 801–805 (1994).
   Google Scholar
• Gao WY, Johns DG, Chokekuchai S, Mitsuya H. Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2', 3'-dideoxynucleoside activities against replication of human immunodeficiency virus. Proc. Natl Acad. Sci. USA 92(18), 8333–8337 (1995).
   Google Scholar
• Fontecave M, Lepoivre M, Elleingand E, Gerez C, Guittet O. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Lett. 421(3), 277–279 (1998).
   PubMed Web of Science ®Google Scholar
• Nakano K, Balint E, Ashcroft M, Vousden KH. A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene 19 (37), 4283–4289 (2000) .
   Google Scholar
• Tanaka H, Arakawa H, Yamaguchi T et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404(6773), 42–49 (2000). Report on the novel gene p53R2.
   Google Scholar
• Lozano G, Elledge SJ. Cancer: p53 sends nucleotides to repair DNA. Nature 404(6773), 24–25 (2000).
   Google Scholar
• Ashcroft M, Vousden KH. Regulation of p53 stability. Oncogene 18(53), 7637–7643 (1999).
   Google Scholar
• Hollstein M, Hergenhahn M, Yang Q, Bartsch H, Wang ZQ, Hainaut P New approaches to understanding p53 gene tumor mutation spectra. Mutat. Res. 431(2), 199–209 (1999).
   Google Scholar
• Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73a and their collaboration to induce apoptosis. Nature 399(6738), 809–813 (1999).
   Google Scholar
• Gong JG, Costanzo A, Yang HQ et al The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature399(6738), 806–809 (1999).
   Google Scholar
• Yuan ZM, Shioya H, Ishiko T et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399(6738), 814–817 (1999).
   Google Scholar