Skip to main content
SpringerLink
Log in

Antimetabolites

  • Chapter
Apoptosis, Senescence, and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

summary

Cell death has been divided into two main types: programmed cell death (PCD), in which the cell plays an active role, and passive (necrotic) cell death. PCD has been categorized into different subtypes: apoptosis, anoikis, mitotic catastrophe, autophagy, paraptosis, and cytoplasmic (for which the mechanism of molecular activation remains unknown). Senescence arrest, accelerated senescence, and differentiation are also responses that can be induced in response to DNA-damaging agents. Considerable attention has been given to the study of apoptotic responses following DNA damage induced in cancer cells by chemotherapeutic agents. Apoptosis may occur as a primary event following chemotherapy in which genes that regulate apoptosis will influence the outcome of therapy or alternatively as an event secondary to the induction of lethal damage that involves the subsequent processing of cellular damage . In the former case, apoptosis may occur early within the first few hours of treatment as observed in cells of hematopoietic origin, whereas for solid tumors, the outcome is less clear . The particular type of response induced is highly dependent on the agent and dose employed, the type of DNA damage induced, as well as the genetic and cellular phenotypes. It has been proposed that apoptosis may play a lesser role in tumor response to radiation in comparison with the induction of cell death through mitotic catastrophe or a senescence-like irreversible growth arrest . However, in comparison with the induction of apoptosis, there is a lack of as much definitive information on other cell death processes that occur in cancer cells in response to chemotherapeutic agents, including antimetabolites. This chapter reviews what is known about these processes at the present time in response to experimental or clinically used agents that are analogs of 5-fluorouracil (FUra), cytidine (Cyd) or purines, hydroxyurea, or that belong to the family of folate antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Castro-Obregon S, Rao RV, del Rio G, Chen SF, Poksay KS, Rabizadeh S, Vesce S, Zhang XK, Swanson RA, Bredesen DE. Alternative, nonapoptotic programmed cell death. J Biol Chem 2004; 279, 17543–17553.

    PubMed  CAS  Google Scholar 

  • Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999; 59:1391–1399.

    PubMed  CAS  Google Scholar 

  • Tannock IF, Lee C. Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs. Br J Cancer 2001; 84, 100–105.

    PubMed  CAS  Google Scholar 

  • Brown M, Wilson G. Apoptosis genes and resistance to cancer therapy. Cancer Biol Ther 2003; 2, 477–490.

    PubMed  CAS  Google Scholar 

  • Gudkov A, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev 2003; 3, 117–129.

    CAS  Google Scholar 

  • Green DR, McGahon A, Martin SJ. Regulation of apoptosis by oncogenes. J Cell Biochem 1996; 60, 33–38.

    PubMed  CAS  Google Scholar 

  • Gajewski TF, Thompson CB. Apoptosis meets signal transduction: elimination of a BAD influence. Cell 1996; 87, 589–592.

    PubMed  CAS  Google Scholar 

  • Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer – a tale of two drugs: implications for biochemical modulation. J Clin Oncol 1997; 15, 368–381.

    PubMed  CAS  Google Scholar 

  • van Laar JA, Rustum YM, Ackland SP, van Groeningen CJ, Peters GJ. Comparison of 5-fluoro-2′-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer. Eur J Cancer 1998; 34, 296–306.

    PubMed  Google Scholar 

  • Schwartzberg L, Petak I, Stewart C, Turner PK, Ashley J, Tillman DM, Douglas L, Mihalik R, Weir A, Tauer K, Shope S, Houghton JA. Modulation of the Fas signaling pathway by interferon-\UPgamma in therapy of colon cancer: phase I trial and correlative studies of interferon-\UPgamma, 5-fluorouracil and leucovorin. Clin Cancer Res 2002; 8, 2488–2498.

    PubMed  CAS  Google Scholar 

  • Houghton JA, Tillman DM, Harwood FG. The ratio of dATP/dTTP influences the commitment of human colon carcinoma cells to thymineless death. Clin Cancer Res 1995; 1, 723–730.

    PubMed  CAS  Google Scholar 

  • Maybaum J, Ullman B, Mandel HG, Day JL, Sadee W. Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. Cancer Res 1980; 40, 4209–4215.

    PubMed  CAS  Google Scholar 

  • Petak I, Tillman DM, Houghton JA. P53-dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin Cancer Res 2000; 6, 4432–4441.

    PubMed  CAS  Google Scholar 

  • Parsels LA, Parsels JD, Wagner LM, Loney TL, Radany EH, Maybaum J. Mechanism and pharmacological specificity of dUTPase-mediated protection from DNA damage and cytotoxicity in human tumor cells. Cancer Chemother Pharmacol 1998; 42, 357–362.

    PubMed  CAS  Google Scholar 

  • Grem JL. 5-Fluorouracil: forty plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18, 299–313.

    PubMed  CAS  Google Scholar 

  • Houghton JA, Houghton PJ, Wooten RS. Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine and 5-fluoro-2′-deoxyuridine. Cancer Res 1979; 39: 2406–2413.

    PubMed  CAS  Google Scholar 

  • Pritchard DM, Watson AJM, Potten CS. Jackman AL, Hickman JA. Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation. Proc Natl Acad Sci USA 1997; 94, 1795–1799.

    PubMed  CAS  Google Scholar 

  • Rustum YM, Cao S. New drugs in colorectal cancer: preclinical studies. Semin Oncol 1999; 26: 612–620.

    PubMed  CAS  Google Scholar 

  • Sobrero A, Guglielmi A, Grossi F, Puglisi F, Aschele C. Mechanism of action of fluoropyrimidines: elevance to the new developments in colorectal cancer chemotherapy. Semin Oncol 2000; 27 (5 Suppl 10):72–77.

    PubMed  CAS  Google Scholar 

  • Geller JI, Szekely-Szucs K, Petak I, Doyle B, Houghton JA. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase (TS) inhibitors in colorectal carcinoma cells. Cancer Res 2004; 64, 6296–6303.

    PubMed  CAS  Google Scholar 

  • Eisold S, Linnebacher M, Ryschich E, Antolovic D, Hinz U, Klar E, Schmidt J. The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines. World J Gastroenterol 2004; 10, 3583–3589.

    PubMed  CAS  Google Scholar 

  • de Angelis PM, Fjell B, Kravik KL, Haug T, Tunheim SH, Reichelt W, Beigi M, Clausen OP, Galteland E, Stokke T. Molecular characterizations of derivatives of HCT116 colorectal cancer cells that are resistant to the chemotherapeutic agent 5-fluorouracil. Int J Oncol 2004; 24, 1279–1288.

    PubMed  Google Scholar 

  • Li WW, Fan J, Hochhauser D, Bertino JR. Overexpressioin of p21waf1 leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. Cancer Res 1997; 57, 2193–2199.

    PubMed  CAS  Google Scholar 

  • Parsels LA, Parsels JD, Tai DC-H, Coughlin DJ, Maybaum J. 5-Fluoro-2′-deoxyuridine-induced cdc25A accumulation correlates with premature mitotic entry and clonogenic death in human colon cancer cells. Cancer Res 2004; 64, 6588–6594.

    PubMed  CAS  Google Scholar 

  • Xiao Z, Xue J, Sowin TJ, Rosenberg SH, Zhang H. A novel mechanism of checkpoint abrogation conferred by chk1 downregulation. Oncogene 2005; 24, 1403–1411.

    PubMed  CAS  Google Scholar 

  • Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K, Wesselborg S. Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 2000; 19, 4563–4573.

    PubMed  CAS  Google Scholar 

  • Adachi Y, Taketani S, Oyaizu H, Ikebukuro K, Tokunaga R, Ikehara S. Apoptosis of colorectal adenocarcinoma induced by 5-FU and/or IFN-gamma through caspase 3 and caspase 8. Int J Oncol 1999; 15, 1191–1196.

    PubMed  CAS  Google Scholar 

  • Wu XX, Kakehi Y, Mizutani Y, Lu J, Terachi T, Ogawa O. Activation of caspase-3 in renal cell carcinoma cells by anthracyclines or 5-fluorouracil. Int J Oncol 2001; 19, 19–24.

    PubMed  CAS  Google Scholar 

  • Petak I, Tillman DM, Harwood FG, Houghton JA. Fas-dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 2000; 60: 2643–2650.

    PubMed  CAS  Google Scholar 

  • Peters GJ, van Triest B, Backus HHJ, Kuiper CM, van der Wilt CL, Pinedo HM. Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor ralitrexed. Eur J Cancer 2000; 36, 916–924.

    Google Scholar 

  • Geller J, Petak I, Szekely Szucs K, Nagy K, Tillman DM, Houghton JA. Interferon-\UPgamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the IAP survivin. Clin Cancer Res 2003; 9, 6504–6515.

    PubMed  CAS  Google Scholar 

  • Petak I, Tillman DM, Harwood FG, Houghton JA. Fas-dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 2000; 60: 2643–2650.

    PubMed  CAS  Google Scholar 

  • Green DR, Beere HM. Killers or clean-up crew: how central are the central mechanisms of apoptosis. In: Apoptosis and Cancer Therapy, Hickman JA and Dive C (eds.), Totowa, NJ: Humana Press Inc., 1999; 157–174.

    Google Scholar 

  • McCarthy NJ, Whyte MKB, Gilbert CS, Evan GI. Inhibition of ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol 1997; 136, 215–227.

    PubMed  CAS  Google Scholar 

  • Houghton JA, Harwood FG, Tillman DM. Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc Natl Acad Sci USA 1997; 94, 8144–8149.

    PubMed  CAS  Google Scholar 

  • Tillman DM, Petak I, Houghton JA. A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 1999; 5: 425–430.

    PubMed  CAS  Google Scholar 

  • Eichhorst ST, Muller M, Li-Weber M, Schulze-Bergkamen H, Angel P, Krammer PH. A novel AP-1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol Cell Biol 2000; 20, 7826–7837.

    PubMed  CAS  Google Scholar 

  • Longley DB, Allen WL, McDermott U, Wilson TR, LAtif T, Boyer J, Lynch M, Johnston PG. The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites. Clin Cancer Res 2004; 10, 3562–3571.

    PubMed  CAS  Google Scholar 

  • Eichhorst ST, Muerkoster S, Weigand MA, Krammer PH. The chemotherapeutic drug 5-fluorouracil induces apoptosis in mouse thymocytes in vivo via activation of the CD95(APO-1/Fas) system. Cancer Res 2001; 61, 243–248.

    PubMed  CAS  Google Scholar 

  • Ciccolini J, Fina F, Bezulier K, Giacometti S, Roussel M, Evrard A, Cuq P, Romain S, Martin P-M, Aubert C. Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, xeloda, is mediated via Fas. Mol Cancer Ther 2002; 1, 923–927.

    PubMed  CAS  Google Scholar 

  • Moller P, Koretz K, Leithauser F, Bruderlein S, Henne C, Quentmeier A, Krammer PH. Expression of APO-1 (CD95), a member of the NGF/TNF receptor superfamily, in normal and neoplastic colon epithelium. Int J Cancer 1994; 57: 371–377.

    PubMed  CAS  Google Scholar 

  • Leithauser F, Dhein J, Mechtersheimer G, Koretz K, Bruderlein S, Henne C, Schmidt A, Debatin KM, Krammer PH, Moller P. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest 1993; 69, 415–429.

    PubMed  CAS  Google Scholar 

  • Iwase M, Watanabe H, kondo G, Ohashi M, Nagumo M. Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil. Int J Cancer 2003; 106, 619–625.

    PubMed  CAS  Google Scholar 

  • Ganten TM, Haas TL, Sykora J, Stahl H, Sprick MR, Fas SC, Krueger A, Weigand MA, Grosse-Wilde A, Stremmel W, Krammer PH, Walczak H. Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitization of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Diff 2004; 11:S86–S96.

    CAS  Google Scholar 

  • Lacour S, Micheau O, Hammann A, Drouineaud V, Tschopp J, Solary E, Dimanche-Boitrel M-T. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 2003; 22, 1807–1816.

    PubMed  CAS  Google Scholar 

  • Naka T, Sugamura K, Hylander BL, Widmer MB, Rustum YM, Repasky EA. Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients’ colon tumors grown in SCID mice. Cancer Res 2002; 62, 5800–5806.

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Nagano H, Sakon M, Wada H, Eguchi H, Kondo M, Damdinsuren B, Ota H, Nakamura M, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Yagita H, Monden M. Partial contribution of tumor necrosis factor-related apootosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against hepatocellular carcinoma. Clin Cancer Res 2004; 10, 7884–7895.

    PubMed  CAS  Google Scholar 

  • Wang S, El-Deiry WS. Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res 2004; 64, 6666–6672.

    PubMed  CAS  Google Scholar 

  • Wang W, Cassidy J. Constitutive nuclear factor-kappa B m RNA, protein overexpression and enhanced DNA-binding activity in thymidylaye synthase inhibitor-resistant tumour cells. Br J Cancer 2003; 88, 624–629.

    PubMed  CAS  Google Scholar 

  • Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NF-\UPkappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer 2003; 104, 504–511.

    PubMed  CAS  Google Scholar 

  • Voboril R, Hochwald SN, Li J, Brank A, Weberova J, Wessels F, Moldawer LL, Camp ER, MacKay SL. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res 2004; 120, 178–188.

    PubMed  CAS  Google Scholar 

  • Uetsuka H, Haisa M, Kimura M, Gunduz M, Kaneda Y, Ohkawa T, Takaoka M, Murata T, Nobuhisa T, Yamatsuji T, Matsuoka J, Tanaka N, Naomoto Y. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell Res 2003; 10, 27–35.

    Google Scholar 

  • Yang JH, Fenf F, Qian H, Cheng H. Chemosensitization of breast carcinoma cells with the use of bcl-2 antisense oligonucleotide. Breast 2004; 13, 227–231.

    PubMed  CAS  Google Scholar 

  • Guo B, Cao S, Toth K, Azrak RG, Rustum YM. Overexpression of Bax enhances antitumor activity of chemotherapeutic agents in human head and neck squamous cell carcinoma. Clin Cancer Res 2000; 6, 718–724.

    PubMed  CAS  Google Scholar 

  • Xu ZW, Freiss H, Buchler MW, Solioz M. Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. Cancer Chemother Pharmacol 2002; 49, 504–510.

    PubMed  CAS  Google Scholar 

  • Pritchard DM, Print C, O’Reilly L, Adams JM, Potten CS, Hickman JA. Bcl-w is an important determinant of damage-induced apoptosis in epithelia of small and large intestine. Oncogene 2000; 19, 3955–3959.

    PubMed  CAS  Google Scholar 

  • Yuan J, Yanker BA. Caspase activity sows the seeds of neuronal death. Nat Cell Biol 1999; 1: E44–E45.

    PubMed  CAS  Google Scholar 

  • Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, Del Rio G, Bredesen DE, Ellerby HM. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 2002; 277, 21836–21842.

    PubMed  CAS  Google Scholar 

  • Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 2002; 277, 34287–34294.

    PubMed  CAS  Google Scholar 

  • Halloran CM, Ghaneh P, Shore S, Greenhalf W, Zumstein L, Wilson D, Neoptolemos JP, Costello E. {%}-Fluorouracil or gemcitabine combined with adenoviral-mediated reintroduction of p16INK4A greatly enhanced cytotoxicityt in Panc-1 pancreatic adenocarcinoma cells. J Gene Med 2004; 6: 514–525.

    PubMed  CAS  Google Scholar 

  • Hsu LC, Lee RM, White RL. The HPV16 E6/E7 oncogene sensitizes human ovarian surface epithelial cells to low-dose but not high-dose 5-FU and 5-FUdR. Biochem Biophys Res Commun 2004; 320, 249–255.

    PubMed  CAS  Google Scholar 

  • Elliott MJ, Farmer MR, Atienza C, Stilwell A, Dong YB, Yang HL, Wong SL, McMasters KM. E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. Tumour Biol 2002; 23, 76–86.

    PubMed  CAS  Google Scholar 

  • Ramsay RG, Micallef S, Lightowler S, Mucenski ML, Mantamadiotis T, Bertoncello I. C-myb heterozygous mice are hypersensitive to 5-fluorouracil and ionizing radiation. Mol Cancer Res 2004; 2, 354–361.

    PubMed  CAS  Google Scholar 

  • Modrak DE, Rodriguez MD, Goldenberg DM, Lew W, Blumenthal RD. Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts. Int J Oncol 2002; 20, 379–384.

    PubMed  CAS  Google Scholar 

  • Tseng YS, Tzeng CC, Chiu AW, Lin CH, Won SJ, Wu IC, Liu HS. Ha-ras overexpression mediated cell apoptosis in the presence of 5-fluorouracil. Exp Cell Res 2003; 288, 403–414.

    PubMed  CAS  Google Scholar 

  • Jin W, Wu L, Liang K, Liu B, Lu Y, Fan Z. Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. Br J Cancer 2003; 89, 185–191.

    PubMed  CAS  Google Scholar 

  • Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res 2002; 62, 6323–6328.

    PubMed  CAS  Google Scholar 

  • Chen WS, Liu JH, Liu JM, Lin JK. Sequence-dependent effect of a cyclooxygenase-2 inhibitor on topoisomerase I inhibitor and 5-fluorouracil-induced cytotoxicity of colon cancer cells. Anticancer Drugs 2004; 15, 287–294.

    PubMed  CAS  Google Scholar 

  • Meyers M, Wagner MW, Hwang H-S, Kinsella TJ, Boothman DA. Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res 2001; 61, 5193–5201.

    Google Scholar 

  • Meyers M, Hwang A, Wagner MW, Boothman DA. Special section: impact of the environment on colon cancer (II): roles of DNA mismatch repair in apoptotic responses to therapeutic agents. Environ Mol Mutagen 2004; 44, 249–264.

    PubMed  CAS  Google Scholar 

  • Schneider HJ, Sampson SA, Cunningham D, Norman AR, Andreyev HJ, Tilsed JV, Clarke PA. Bcl-2 expression and response to chemotherapy in colorectal adenocarcinomas. Br J Cancer 1997; 75, 427–431.

    PubMed  CAS  Google Scholar 

  • Paradiso A, Simone G, Lena MD, Leone B, Vallejo C, Lacava J, Dellapasqua S, Daidone MG, Costa A. Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer. Br J Cancer 2001; 84, 651–658.

    PubMed  CAS  Google Scholar 

  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275, 967–969.

    PubMed  CAS  Google Scholar 

  • Ouyang H, Furukawa T, Abe T, Kato Y, Horii A. The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. Clin Cancer Res 1998; 4, 1071–1074.

    PubMed  CAS  Google Scholar 

  • Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 2000; 97, 10872–10877.

    PubMed  CAS  Google Scholar 

  • Schelwies K, Sturm I, Grabowski P, Scherubl H, Schindler I, Hermann S, Stein H, Huhr H-J, Riecken EO, Zeitz M, Dorken B, Daniel PT. Analysis of P53/BAX in primary colorectal carcinoma: low BAX protein expression is a negative prognostic factor in UICC stage III tumors. Int J Cancer 2002; 99, 589–596.

    PubMed  CAS  Google Scholar 

  • Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80, 293–299.

    PubMed  CAS  Google Scholar 

  • Sturm I, Kohne C-H, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dorken B, Daniel PT. Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 1999; 17, 1364–1374.

    PubMed  CAS  Google Scholar 

  • Sarela A, Scott N, Ramsdale J, Markham AF, Guilou PJ. Immunohistochemical detection of the anti-apoptosis protein, survivin, predicts survival after curative resection of stage II colorectal carcinomas. Ann Surg Oncol 2001; 8, 305–310.

    PubMed  CAS  Google Scholar 

  • Rodel F, Hoffmann J, Grabenbauer GG, Papadopoulos T, Weiss C, Gunther K, Schick C, Sauer R, Rodel C. High survivin expression is associated with reduced apoptosis in rectal cancer and may predict disease-free survival after preoperative radiochemotherapy and surgical resection. Strahlenther Onkol 2002; 178, 426–435.

    PubMed  Google Scholar 

  • Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 1998; 58, 5071–5074.

    PubMed  CAS  Google Scholar 

  • Takamizawa S, Scott D, Wen J, Grundy P, Bishop W, Kimura K, Sandler A. The survivin:fas ratio in pediatric renal tumors. J Pediatr Surg 2001; 36, 37–42.

    PubMed  CAS  Google Scholar 

  • Sandler A, Scott D, Azuhata T, Takamizawa S, O’Dorisio S. The survivin:Fas ratio is predictive of recurrent disease in neuroblastoma. J Pediatr Surg 2002; 37, 507–511.

    PubMed  Google Scholar 

  • Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA, Zangemeister-Wittke U. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cells to chemotherapy. Cancer Res 2000; 60, 2805–2809.

    PubMed  CAS  Google Scholar 

  • Kufe D, Spriggs D, Egan EM, Munroe D. Relationships among Ara-CTP pools, formation of (Ara-C) DNA, and cytotoxicity of human leukemic cells. Blood 1984; 64; 54–58.

    PubMed  CAS  Google Scholar 

  • Mansson E, Paul A, Lofgren C, Ullberg K, Paul C, Eriksson S, Albertioni F. Cross-resistance to cytosine arabinoside in a multidrug-resistant human promyelocytic cell line selected for resistance to doxorubicin: implications for combination chemotherapy. Br J Haematol 2001: 114:557–565.

    PubMed  CAS  Google Scholar 

  • Aciwa H, Oguri T, Sato S, Maeda H, Niimi T, Ueda R. Determinants of sensitivity and resistance to gemcitabine: the roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non-small cell lung cancer. Cancer Sci 2004; 95, 753–757.

    Google Scholar 

  • Galmarini CM, Clrke ML, Jordheim L, Santos CL, Cros E, Mackey JR, Dumontet C. Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene. BMC Pharmacol 2004; 4:8.

    PubMed  Google Scholar 

  • Duxbury MS, Hiromichi I, Zinner MJ, Ashley SW, Whang EE. RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Oncogene 2004; 23, 1539–1548.

    PubMed  CAS  Google Scholar 

  • Kanno S, Higurashi A, Watanabe Y, Shouji A, Asou K, Ishikawa M. Susceptibility to cytosine arabinoside (Ara-C)-induced cytotoxicity in human leukemia cell lines. Toxicol Lett 2004; 152:149–158.

    PubMed  CAS  Google Scholar 

  • Chen M, Hough AM, Lawrence TS. The role of p53 in gemcitabine-mediated cytotoxicity and radio sensitization. Cancer Chemother Pharmacol 2000; 45, 369–374.

    PubMed  CAS  Google Scholar 

  • Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H. Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int J Cancer 2004; 109, 182–188.

    PubMed  CAS  Google Scholar 

  • Wang Z, Wang S, Dai Y, Grant S. Brostatin 1 increases 1-β-D-arabinofuranosylcytosine-induced cytochrome c release and apoptosis in human leukemia cells ectopically expressing Bcl-xL. J Pharmacol Exp Ther 2002; 301, 568–577.

    Google Scholar 

  • Tang L, Boise LH, Dent P, Grant S. Potentiation of 1-β-D-arabinofuranosylcytosine-mediated mitochondrial damage and apoptosis in human leukemia cells (U937) overexpressing Bcl-2 by the kinase inhibitor 7-hydroxystaurosporine (UCN-01). Biochem Pharmacol 2000; 60, 1445–1456.

    PubMed  CAS  Google Scholar 

  • Kim CN, Wang X, Huang Y, Ibrado AM, Liu L, Fang G, Bhalla K. Overexpression of Bcl-x(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. Cancer Res 1997; 57, 3115–3120.

    PubMed  CAS  Google Scholar 

  • Chang G-C, Hsu S-L, Tsai J-R, Wu W-J, Chen C-Y, Sheu G-T. Extracellular signal-regulated kinase activation and Bcl-2 downregulation mediate apoptosis after gemcitabine treatment partly via a p53-independent pathway. Eur J Pharmacol 2004; 502, 169–183.

    PubMed  CAS  Google Scholar 

  • Xu Z, Freiss H, Solioz M, Aebi S, Korc M, Kleef J, Buchler MW. Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine. Int J Cancer 2001; 94, 268–274.

    PubMed  CAS  Google Scholar 

  • Konopleva M, Tari AM, Estrov Z, Harris D, Xie Z, Zhao S, Lopez-Berestein G, Andreef M. Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood 2001; 95, 3929–3938.

    Google Scholar 

  • Vrana JA, Bieszczad CK, Cleveland ES, Ma Y, Park JP, Mohandas TK, Craig RW. An MCL-1-overexpressing Burkitt lymphoma subline exhibits enhanced survival on nexpopsure to serum deprivation, topoisomerase inhibitors, or staurosporine but remains sensitive to 1-beta-D-arabinofuranosylcytosine. Cancer Res 2002; 62, 892–900.

    PubMed  CAS  Google Scholar 

  • Shi X, Liu S, Kleeff J, Freiss H, Buchler MW. Acquired resistance of pancreatic cancer cells towards 5-fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology 2002; 62, 354–362.

    PubMed  CAS  Google Scholar 

  • Lock RB and Stribinskene L. Dual modes of cell death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival. Cancer Res 1996; 56, 4006–4012.

    Google Scholar 

  • Amarante-Mendes GP, Finucane DM, Martin SJ, Cotter TG, Salvesen GS, Green DR. Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death. Cell Death Diff 1998; 4, 298–306.

    Google Scholar 

  • Ng SSW, Tsao M-S, Chow S, Hadley DW. Inhibition of phosphatidylinositide 3-kinase enhances gencitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 2000; 60, 5451–5455.

    PubMed  CAS  Google Scholar 

  • Ng SS, Tsao MS, Nicklee T, Hedley DW. Wortmannin inhibits pkb/akt phosphorylation and promotes gencitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res 2001; 7, 3269–3275.

    PubMed  CAS  Google Scholar 

  • Yokoi K, Fidler IJ. Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine. Clin Cancer Res 2004; 10, 2299–2306.

    PubMed  CAS  Google Scholar 

  • Yu C, Wang Z, Dent P, Grant S. MEK1/2 inhibitors promote Ara-C-induced apoptosis but not loss in \UPDelta\UPPsim in HL-60 cells. Biochem Biophys Res Commun 2001; 286, 1011–1018.

    PubMed  CAS  Google Scholar 

  • Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, Konopleva M, Zhao S, Estey E, Andreeff M. Therapeutic targeting of the MEKK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 2001; 108, 851–859.

    PubMed  CAS  Google Scholar 

  • Habiro A, Tanno S, Koizumi K, Izawa T, Nakano Y, Osanai M, Mizukami Y, Okumura T, Kohgo Y. Involvement of p38 mitogen-activated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells. Biochem Biophys Res Commun 2004; 316, 71–77.

    PubMed  CAS  Google Scholar 

  • Jarvis WD, Fornari FA, Tombes RM, Erukulla RK, Bittman R, Schwartz GK, Dent P, Grant S. Evidence of involvement of mitogen-activated protein kinase, rather than stress-activated protein kinase, in potentiation of 1-β-D-arabinofuranosylcytosine-induced apoptosis by interruption of protein kinase C signaling. Mol Pharmacol 1998; 54, 844–856.

    PubMed  CAS  Google Scholar 

  • Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Inhibition of Src tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clin Cancer Res 2004; 10, 2307–2318.

    PubMed  CAS  Google Scholar 

  • Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. SiRNA directed against s-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity. J Am Coll Surg 2004; 198, 953–959.

    PubMed  Google Scholar 

  • Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR, Schafer H. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 2003; 22, 3243–3251.

    PubMed  CAS  Google Scholar 

  • Jones DR, Broad RM, Comeau LD, Parsons SJ, Mayo MW. Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation.\break J Thorac Cardiovasc Surg 2002; 123, 310–317.

    Google Scholar 

  • Romano MF, Lamberti A, Bisogni R, Tassone P, Pagnini D, Storti G, Del Vecchio L, Turco MC, Venuta S. Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-kappa B-Rel-specific decoy oligodeoxynucleotides. Gene Ther 2000; 7, 1234–1237.

    PubMed  CAS  Google Scholar 

  • Denlinger CE, Rundall BK, Keller MD, Jones DR. Proteasome inhibition sensitizes non-small-cell lung cancer to gemcitabine-induced apoptosis. Ann Thorac Surg 2004; 78, 1207–1214.

    PubMed  Google Scholar 

  • Zheng B, Georgakis GV, Li Y, Bharti A, McConkey D, Aggarwal BB, Younes A. Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-\UPkappa B mutations or activation of the CD30, CD40, and RANK receptors. Clin Cancer Res 2004; 10, 3207–3215.

    PubMed  CAS  Google Scholar 

  • Kamat AM, Karashima T, Davis DW, Lashinger L, Bar-Eli M, Millikan R, Shen Y, Dinney CPN, McConkey DJ. The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo. Mol Cancer Ther 2004; 3, 279–290.

    PubMed  CAS  Google Scholar 

  • Meli M, Tolomeo M, D’Alessandro N, Grimaudo S, Notarbartolo M, Papoff G, Ruberti G, Rausa L, Dusonchet L. Resiatance to gemcitabine in a lymphoma cell line resistant to Fas-mediated apoptosis. Anticancer Res 2004; 24, 851–857.

    PubMed  CAS  Google Scholar 

  • Ferreira CG, Tolis C, Span SW, Peters GJ, van Lopik T, Kummer AJ, Pinedo HM, Giaccone G. Drug-induced apoptosis in lung cancer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway. Clin Cancer Res 2000; 6, 203–212.

    PubMed  CAS  Google Scholar 

  • Liu W, Bodle E, Chen JY, Gao M, Rosen GD, Broaddus VC. Tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in mesothelioma cell lines. Am J Respir Cell Mol Biol 2001; 25, 111–118.

    PubMed  CAS  Google Scholar 

  • Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene 2003; 22, 7512–7523.

    PubMed  CAS  Google Scholar 

  • Glover AB, Leyland-Jones BR, Chun HG, Davies B, Hoth DF. Acacitidine: 10 years later. Cancer Treat Rep 1987; 71, 737–746.

    PubMed  CAS  Google Scholar 

  • Momparler RL, Cote S, Eliopoulos N. Pharmacological approach for optimization of the dose schedule of 5-aza-2′-deoxycytidine (decitabine) for the therapy of leukemia. Leukemia 1997; 11, 175–180.

    PubMed  CAS  Google Scholar 

  • Durant ST, Morris MM, Illand M, McKay HJ, McCormick C, Hirst GL, Borts RH, Brown R. Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes. Curr Biol 1999; 9, 51–54.

    PubMed  CAS  Google Scholar 

  • Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 2000; 60, 6039–6044.

    PubMed  CAS  Google Scholar 

  • Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene 1999; 18, 2335–2341.

    PubMed  CAS  Google Scholar 

  • Teitz T, Lahti JM, Kidd VJ. Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. J Mol Med 2001; 79, 428–436.

    PubMed  CAS  Google Scholar 

  • Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ho R, Ikegaki N, Brodeur GM. Resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 2001; 61, 1314–1319.

    PubMed  CAS  Google Scholar 

  • Hopkins-Donaldson S, Bodmer J-L, Bourland KB, Brognara CB, Tschopp J, Gross N. Loss of caspase-8 expression in neuroblastoma is related to malignancy and resistance to TRAIL-induced apoptosis. Med Pediatr Oncol 2000; 35, 608–611.

    PubMed  CAS  Google Scholar 

  • Fulda S, Kufer MU, Meyer E, van Halen F, Dockhorn-Dworniczak B, Debatin K-M. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 2001; 20, 5865–5877.

    PubMed  CAS  Google Scholar 

  • Grotzer MA, Eggert A, Zuzak TJ, Janss Aj, Marwaha S, Wiewrodt BR, Ikegaki N, Brodeur GM, Phillips PC. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 2000; 19, 4604–4610.

    PubMed  CAS  Google Scholar 

  • Gomyo Y, Sasaki J, Branch C, Roth JA, Mukhopadhyay T. 5-Aza-2′-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells. Oncogene 2004; 23, 6779–6787.

    PubMed  CAS  Google Scholar 

  • Ueki T, Takeuchi T, Nishimatsu H, Kajiwara T, Moriyama N, Narita Y, Kawabe K, Ueki K, Kitamura T. Silencing of the caspase-1 gene occurs in murine and human renal cancer cells and causes solid tumor growth in vivo. Int J Cancer 2001; 91, 673–679.

    PubMed  CAS  Google Scholar 

  • Cheson BD, Grever MR. Clinical development of 2′ deoxycoformycin. In: Nucleoside Analogs in Cancer Therapy, Cheson BD, Keating MJ, Plunket W (eds), New York: Marcel Dekker, 1997; 95–112.

    Google Scholar 

  • Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reveral strategies. Leukemia 2001; 15, 875–890.

    PubMed  CAS  Google Scholar 

  • Pettitt A. mechanism of action of purine analogues in chronic lymphocytic leukaemia. Br J Hematol 2003; 121, 692–702.

    CAS  Google Scholar 

  • Kawasaki H, CArrera CJ, Piro LD, Saven A, Kipps TJ, Carson DA. Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 20 chlorodeoxyadenosine. Blood 1993; 81, 597–601.

    PubMed  CAS  Google Scholar 

  • Seto S, CArrera CJ, Kubota M, Wasson DB, Carson DA. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 1985; 75: 377–383.

    PubMed  CAS  Google Scholar 

  • Robertson LE, Chubb S, Meyn RE, Story M, Ford R, Hittelman WN, Plunkett W. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-beta-D-arabinosyl-2-fluoroadenine. Blood 1993; 81, 143–150.

    PubMed  CAS  Google Scholar 

  • Huang P, Plunkett W. Fludarabine- and gemcitabine-induced apoptosis: incorporation of analogs into DNA as a critical event. Cancer Chemther Pharmacol 1995; 36, 181–188.

    CAS  Google Scholar 

  • Huang P, Robertson LE, Wright LS, Plunkett W. High molecular weight DNA fragmentation: a critical event in nucleoside analogue-induced apoptosis in leukemia cells. Clin Cancer Res 1995; 1, 1005–1013.

    PubMed  CAS  Google Scholar 

  • Huang P, Ballal K, Plunkett W. Biochemical characterization of the protein activity responsible for high molecular weight DNA fragmentation during drug-induced apoptosis. Cancer Res 1997; 57, 3407–3414.

    PubMed  CAS  Google Scholar 

  • Belosillo B, Dalmau M, Colomer D, Gil J. Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells. Blood 1997; 89, 3378–3384.

    Google Scholar 

  • Pettitt AR, Cawley JC. Caspases influence the mode but not the extent of cell death induced by purine analogues in chronic lymphocytic leukaemia. Br J Haematol 2000; 109, 800–804.

    PubMed  CAS  Google Scholar 

  • Perez-Galan P, Marzo I, Giraldo P, Rubio-Felix D, Lasierra P, Larrad L, Anel A, Naval J. Role of caspases and apoptosis-inducing factor (AIF) in cladribine-induced apoptosis of B cell chronic lymphocytic leukemia. Leukemia 2002; 16, 2106–114.

    PubMed  CAS  Google Scholar 

  • Sampath D, Plunkett W. The role of c-Jun kinase in the apoptotic response to nucleoside analogue-induced DNA damage. Cancer Res 2000; 60, 6408–6415.

    PubMed  CAS  Google Scholar 

  • Achanta G, Pelicano H, Feng L, Plunkett W, Huang P. Interaction of p53 and DNA-PK in response to nucleoside analogues: potential role as a sensor complex for DNA damage. Cancer Res 2001; 61, 8723–8729.

    PubMed  CAS  Google Scholar 

  • Romano MF, Lamberti A, Turco MC, Venuta S. CD40 and B chronic lymphocytic leukemia cell response to fludarabine: the influence of NF-kappaB/Rel transcription factors on chemotherapy-induced apoptosis. Leuk Lymph 2000; 36, 255–262.

    CAS  Google Scholar 

  • de la Fuente MT, Casanove B, Moyano JV, Garcia-Gila M, Sanz L, Garcia-Marco J, Silva A, Garcia-Pardo A. Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. J Leukoc Biol 2002; 71, 495–502.

    PubMed  Google Scholar 

  • Pepper C, Thomas A, Hidalgo de Quintana J, Davies S, Hoy T, Bentley P. Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia: the role of Bcl-2 family dysregulation. Leuk Res 1999; 23, 1007–1014.

    PubMed  CAS  Google Scholar 

  • Morales AA, Olsson A, Celsing F, Osterborg A, Jondal M, Osorio LM. High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia. Int J Cancer 2005; 113, 730–737.

    PubMed  CAS  Google Scholar 

  • Bosanquet AG, Sturm I, Wieder T, Essmann F, Bosanquet MI, Head DJ, Dorken B, Daniel PT. Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia. Leukemia 2002; 16, 1035–1044.

    PubMed  CAS  Google Scholar 

  • Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, Wang HG, Zhang X, Bullrich F, Croce CM, Rai K, Hines J, Reed JC. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91, 3379–3389.

    PubMed  CAS  Google Scholar 

  • Estlin EJ. Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia. Br J Haematol 2000; 110, 29–40.

    PubMed  CAS  Google Scholar 

  • Estlin EJ. Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine. Cancer Treat Rev 2001; 27: 351–363.

    PubMed  CAS  Google Scholar 

  • Krynetski EY, Krynetskaia NF, Yanishevski Y, Evans WE. Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase. Mol Pharmacol 1995; 47, 1141–1147.

    PubMed  CAS  Google Scholar 

  • Fink D, Abei S, Howell SB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res 1998; 4, 1–6.

    PubMed  CAS  Google Scholar 

  • Hande KR, Garrow JC. Purine antimetabolites. In: Cancer Chemotherapy and Biotherapy, Principle and Practice, 2nd ed, Chabner BA, Longo DL (eds), Philadelphia, PA: Lippincott JB & Company, 1996; 235–252.

    Google Scholar 

  • Zimm S, Johnson GE, Chabner BA, Poplack DG. Cellular pharmacokinetics of mercaptopurine in human neoplastic cells and cell lines. Cancer Res 1985; 45, 4156–4161.

    PubMed  CAS  Google Scholar 

  • Hortelano S, Dallaporta B, Zamzami N, Hirsch T, Susin SA, Marzo I, Bosca L, Kroemer G. Nitric oxide induces apoptosis via triggering mitochondrial permeability transition. FEBS Lett 1997; 410, 373–377.

    PubMed  CAS  Google Scholar 

  • el Alaoui S, Lawry J, Griffin M. The cell cycle and induction of apoptosis in a hamster fibrosarcoma cell line treated with anti-cancer drugs: its importance to solid tumour chemotherapy. J Neurooncol 1997; 31, 195–207.

    PubMed  CAS  Google Scholar 

  • Hortelano S, Bosca L. 6-Mercaptopurine decreases the Bcl-2/Bax ratio and induces apoptosis in activated splenic B lymphocytes. Mol Pharmacol 1997; 51, 414–421.

    PubMed  CAS  Google Scholar 

  • Young HS, Khan AS, Kendra JR, Coulson IH. The cutaneous side-effects of hydroxyurea. Clin Lab Haematol 2000; 22, 229–232.

    PubMed  CAS  Google Scholar 

  • Severin I, Padieu M, Lhuguenot J-C, Chagnon M-C. Toxic interaction between hydroxyurea and 1-β-D-arabino-furanosylcytosine on the DNA of a human hepatoma cell line (HEPG2). Toxicol Lett 2003; 145, 303–311.

    PubMed  CAS  Google Scholar 

  • Huyghe P, Dassonneville L, Fenaux P, Bailly C. Hydroxyurea-induced apoptosis in an EBV-immortalized lymphoblastoid cell line. Oncol Res 2004; 14, 235–245.

    PubMed  Google Scholar 

  • Longo-Sorbello GSA, Bertino JR. Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials. Hematologica 2001; 86, 121–127.

    CAS  Google Scholar 

  • Barry MA, Behnke CA, Eastman A. Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 1990; 40, 2353–2362.

    PubMed  CAS  Google Scholar 

  • Kaufmann S. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 1989; 49, 5870–5878.

    PubMed  CAS  Google Scholar 

  • de Silva CP, de Oliveira CR, de Conceicao PL. Apoptosis as a mechanism of cell death induced by different chemotherapeutic drugs in human leukemic T-lymphocytes. Biochem Pharmacol 1996; 51, 1331–1340.

    PubMed  Google Scholar 

  • Hattangadi DK, DeMasters GA, Walker TD, Jones KR, Di X, Newsham IF, Gewirtz DA. Influence of p53 and caspase 3 activity on cell death and sensescence in response to methotrexate in the breast tumor cell. Biochem Pharmacol 2004; 68, 1699–1708.

    PubMed  CAS  Google Scholar 

  • Papaconstantinou HT, Xie C, Zhang W, Ansari NH, Hellmich MR, Townsend CM, Ko TC. The role of caspases in methotrexate-induced gastrointestinal toxicity. Surgery 2001; 859–865.

    Google Scholar 

  • Caltayud S, Warner TD, Mitchell JA. Modulation of colony stimulating factor release and apoptosis in human colon cancer cells by anticancer drugs. Br J Cancer 2002; 86, 1316–1321.

    Google Scholar 

  • Evdokiou A, Bouralexix S, Atkins GJ, Chai F, Hay S, Clayer M, Findlay DM. Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. Int J Cancer 2002; 99, 491–504.

    PubMed  CAS  Google Scholar 

  • Mizutani Y, Yoshida O. Effect of anticancer agents on Fas-mediated cytotoxicity against bladed cancer cells. J Infect Chemother 1999; 5, 139–143.

    PubMed  CAS  Google Scholar 

  • Valentijn AJ, Zouq N, Gilmore AP. Anoikis. Biochem Soc Trans 2004; 32, 421–425.

    PubMed  CAS  Google Scholar 

  • Sreedhar AS, Csermely P. Heat shock proteins in the regulation of apoptosis: new strategies in tumor therapy. A comprehensive review. Pharmacol Ther 2004; 101, 227–257.

    PubMed  CAS  Google Scholar 

  • Broker LE, Kruyt FAE, Giaccone G. Dell death independent of caspases: a review. Clin Cancer Res 2005; 11, 3155–3162.

    PubMed  Google Scholar 

  • Roninson IB, Broude EV, Chang B-D. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updates 2001; 4, 303–313.

    CAS  Google Scholar 

  • Ianzini F, Mackey MA. Spontaneous premature chromatin condensation and mitotic catastrophe following irradiation of HeLa S3 cells. Int J Radiat Biol 1997; 72, 409–421.

    PubMed  CAS  Google Scholar 

  • Mackey MA, Zhang XF, Hunt CR, Sullivan SJ, Blum J, Laszlo A. Uncoupling of M-phase kinase activation from the completion of S-phase by heat shock. Cancer Res 1996; 56, 1770–1774.

    PubMed  CAS  Google Scholar 

  • Chang B-D, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 1999; 59, 3761–3767.

    PubMed  CAS  Google Scholar 

  • Touneki O, Pron G, Belehradek J, Mir LM. Bleomycin, an apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. Cancer Res 1993; 53: 5462–5469.

    Google Scholar 

  • Torres K, Horwitz SB. Mechanisms of taxol-induced cell death are concentration-dependent. Cancer Res 1998; 58, 3620–3626.

    PubMed  CAS  Google Scholar 

  • Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, Ogier-Denis E. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 2001; 276, 35243–35246.

    PubMed  CAS  Google Scholar 

  • Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004; 306, 990–995.

    PubMed  CAS  Google Scholar 

  • Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304, 1500–1502.

    PubMed  CAS  Google Scholar 

  • Nelson DA, White E. Exploiting different ways to die. Genes Dev 2004; 18, 1223–1226.

    PubMed  CAS  Google Scholar 

  • Wang Y, Li X, Wang L, Ding P, Zhang Y, Han W, Ma D. An alternative form of paraptosis-like cell death, triggered by TAJ/TROY and enhanced by PDCD5 overexpression. J Cell Sci 2004; 117, 1525–1532.

    PubMed  CAS  Google Scholar 

  • Sperandio S, Poksay K, de Belle I, Lafuente MJ, Liu B, Nasir J, Bredesen DE. Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Diff 2004; 11, 1066–1075.

    CAS  Google Scholar 

  • Majno G, Joris I. Apoptosis, oncosis, and necrosis: an overview of cell death. Am J Pathol 1995; 146, 3–15.

    PubMed  CAS  Google Scholar 

  • Matsuo A, Watanabe A, Takahashi T, Futamura M, Mori S, Sugiyama Y, Takahashi Y, Saji S. A simple method for classification of cell death by use of thin layer collagen gel for the detection of apoptosis and/or necrosis after cancer chemotherapy. Jpn J Cancer Res 2001; 92, 813–820.

    PubMed  CAS  Google Scholar 

  • Columbano A. Cell death: current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. J Cell Biochem 1995; 58, 181–190.

    PubMed  CAS  Google Scholar 

  • Chang B-D, Xuan Y, Broude EV, Zhu H, Schott B, Fang J, Roninson IB. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 1999; 18, 4808–4818.

    PubMed  CAS  Google Scholar 

  • Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 1998; 16, 1113–1123.

    PubMed  CAS  Google Scholar 

  • Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 1998; 12, 2997–3007.

    PubMed  CAS  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88, 593–602.

    PubMed  CAS  Google Scholar 

  • Blagosklonny MV. Prospective strategies to enforce selectively cell death in cancer cells. Oncogene 2004; 23, 2967–2975.

    PubMed  CAS  Google Scholar 

  • Roninson IB. Tumor cell senescence in cancer treatment. Cancer Res 2003; 63, 2705–2715.

    PubMed  CAS  Google Scholar 

  • Wang Z, Wang S, Fisher PB, Dent P, Grant S. Evidence of a functional role for the cyclin-dependent kinase inhibitor p21CIP1 in leukemic cell (U937) differentiation induced by low concentrations of 1-beta-D-arabinofuranosylcytosine. Differentiation 2000; 66, 1–13.

    PubMed  CAS  Google Scholar 

  • Niitsu N, Ishii Y, Matsuda A, Honma Y. Induction of differentiation of acute promyelocytic leukemia cells by a cytidine deaminase-resistant analogue of 1-beta-D-arabinofuranosylcytosine, 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytidine. Cancer Res 2001; 61, 178–185.

    PubMed  CAS  Google Scholar 

  • Poirier F, Bourin P, Bladier D, Joubert-Caron R, Caron M. Effect of 5-azacytidine and galectin-1 on growth and differentiation of the human b lymphoma cell line bl36. Cancer Cell Int 2001; 1:2.

    Google Scholar 

  • Suh SI, Pyun HY, Cho JW, Baek WK, Park JB, Kwon T, Park JW, Suh MH, Carson DA. 5-Aza-2′-deoxycytidine leads to down-regulation of aberrant p16INK4A RNA transcripts and restores the functional retinoblastoma protein pathway in hepatocellular carcinoma cell lines. Cancer Lett 2000; 160, 81–88.

    PubMed  CAS  Google Scholar 

  • Niitsu N, Hayashi Y, Sugita K, Honma Y. Sensitization by 5-aza-2′-deoxycytidine of leukaemia cells with MLL abnormalities to induction of differentiation by all-trans retinoic acid and 1alpha, 25-dihydroxyvitamin D3. Br J Haematol 2001; 112, 315–326.

    PubMed  CAS  Google Scholar 

  • Michishita E, Nakabayashi K, Suzuki T, Kaul SC, Ogino H, Fujii M, Mitsui Y, Ayusawa D. 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species. J Biochem (Tokyo) 1999; 126, 1052–1059.

    CAS  Google Scholar 

  • Suzuki T, Minagawa S, Michishita E, Ogino H, Fujii M, Mitsui Y, Ayusawa D. Induction of senescence-associated genes by 5-bromodeoxyuridine in HeLa cells. Exp Gerontol 2001; 36: 465–474.

    PubMed  CAS  Google Scholar 

  • Kwak IH, Kim HS, Choi OR, Ryu MS, Lim IK. Nuclear accumulation of globular actin as a cellular senescence marker. Cancer Res 2004; 64, 572–580.

    PubMed  CAS  Google Scholar 

  • Rebbaa A, Zheng X, Chou PM, Mirkin BL. Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene 2003; 22, 2805–2811.

    PubMed  CAS  Google Scholar 

  • te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 2002; 62, 1876–1883.

    Google Scholar 

Download references

Authors
  1. Janet A. Houghton PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacology and Toxicology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA

    David A. Gewirtz

  2. Departments of Medicine, Pharmacology and Toxicology, Biochemistry and Massey Cancer Center, Virginia Commonwealth, Richmond, VA

    Shawn E. Holt

  3. Departments of Pathology, Human Genetics, Pharmacology and Toxicology, Biochemistry and Massey Cancer Center, Virginia Commonwealth, Richmond, VA

    Steven Grant

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this chapter

Cite this chapter

Houghton, J.A. (2007). Antimetabolites. In: Gewirtz, D.A., Holt, S.E., Grant, S. (eds) Apoptosis, Senescence, and Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-221-2_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-221-2_19

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-527-9

  • Online ISBN: 978-1-59745-221-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation