Skip to main content
SpringerLink
Log in

De Novo and Acquired Resistance to Antitumor Alkylating Agents

  • Chapter
Cancer Drug Resistance

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

Abstract

Delineating mechanisms that mediate de novo and acquired resistance to alkylating agents could potentially lead to novel targets for improving the efficacy of this important class of anticancer drugs. De novo resistance is likely to contribute to minimal residual disease and the subsequent emergence of a more permanent form of drug resistance referred to as acquired drug resistance. The tumor microenvironment represents a rich source of both soluble factors and components of extracellular matrixes, both of which can favor cell survival following drug exposure. Experimental evidence suggests signals that originate from the tumor microenvironment are likely to contribute to de novo resistance and thereby facilitate the emergence of acquired resistance. DNA repair pathways, cell cycle checkpoints, drug metabolism, transporters, and alterations in the apoptotic machinery represent potential mechanisms of resistance to alkylating agents. The role of these pathways in conferring acquired and de novo resistance will be discussed in detail this chapter.

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 249.99
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

  1. Dalton WS, Salmon SE. Drug resistance in myeloma: mechanisms and approaches to circumvention. Hematol Oncol Clin North Am 1992; 6:383–393.

    PubMed  CAS  Google Scholar 

  2. Hazlehurst LA, Foley NE, Gleason-Guzman MC, et al. Multiple mechanisms confer drug-resistance to mitoxantrone in the human 8226 myeloma cll line. Cancer Res 1999; 59:1021–1028.

    PubMed  CAS  Google Scholar 

  3. Hazlehurst LA, Enkemann S, Beam CAR, et al. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res 2003; 56:660–670.

    Google Scholar 

  4. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93:1658–1667.

    PubMed  CAS  Google Scholar 

  5. Hazlehurst LA, Damiano JS, Buyuksalm I, Pledger WJ, Dalton WS. Adhesion to fibronectin regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 2000; 38:4319–4327.

    Article  Google Scholar 

  6. Hazlehurst LA, Dalton WS. Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev 2001; 20:43–50.

    Article  PubMed  CAS  Google Scholar 

  7. Hazlehurst LA, Valkov N, Wisner L, et al. Reduction in drug-induced DNA double strand-breaks associated with β1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 2001; 98:1897–1903.

    Article  PubMed  CAS  Google Scholar 

  8. Damiano JS, Hazlehurst LA, Dalton WS. Cell adhesion mediated resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition cyctoxic drugs and ?radiation. Leukemia 2001; 15:1232–1239.

    Article  PubMed  CAS  Google Scholar 

  9. Taylor CW, Dalton WS, Parrish PR, et al. Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line. Br J Cancer 1991; 63:923–929.

    PubMed  CAS  Google Scholar 

  10. Dalton WS, Durie BG, Alberts DS, Gerlach JH, Cress AE. Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein. Cancer Res 1986; 46:5125–5130.

    PubMed  CAS  Google Scholar 

  11. Teicher B A, Herman TS, Holden SA, et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 1990; 247:1457–1460.

    Article  PubMed  CAS  Google Scholar 

  12. Gilman A. The initial clinical trial of nitrogen mustard. Am J Surg 1963; 105:574–578.

    Article  PubMed  CAS  Google Scholar 

  13. Zwelling LA, Michaels S, Schwartz H, Dobson PP, Kohn KW. DNA cross-linking as an indicator of sensitivity and resistance of mouse L1210 leukemia to c is-diamminedichloroplatinumII and L-phenyla-lanine mustard. Cancer Res 1981; 41:640–649.

    PubMed  CAS  Google Scholar 

  14. Spanswick VJ, Craddock C, Sekhar M, et al. Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood 2002; 100:224–229.

    Article  PubMed  CAS  Google Scholar 

  15. Torres-Garcia SJ, Cousineau L, Caplan S, Panasci L. Correlation of resistance to nitrogen mustards in chronic lymphocytic leukemia with enhanced removal of melphalan-inducedDNA cross-links. Biochem Pharmacol 1989; 38:3122–3123.

    Article  PubMed  CAS  Google Scholar 

  16. D’Andrea AD. The Fanconi Anemia/BRCA signaling pathway: disruption in cisplatin-sensitive ovarian cancers. Cell Cycle 2003; 2:290–292.

    PubMed  CAS  Google Scholar 

  17. Olopade OI, Wei M. FANCF methylation contributes to chemoselectivity in ovarian cancer. Cancer Cell 2003; 3:417–420.

    Article  PubMed  CAS  Google Scholar 

  18. Ishida R, Buchwald M. Susceptibility of Fanconi’s anemia lymphoblasts to DNA-cross-linking and alkylating agents. Cancer Res 1982; 42:4000–4006.

    PubMed  CAS  Google Scholar 

  19. D’Andrea AD, Grompe M. Molecularbiology of Fanconi anemia: implications for diagnosis and therapy. Blood 1997; 90:1725–1736.

    PubMed  CAS  Google Scholar 

  20. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002; 297:606–609.

    Article  PubMed  CAS  Google Scholar 

  21. Garcia-Higuera I, Taniguchi T, Ganesan S, et al. Interaction of the Fanconi anemia proteins andBRCA1 in a common pathway. Mol Cell 2001; 7:249–262.

    Article  PubMed  CAS  Google Scholar 

  22. Li S, Ku CY, Farmer AA, Cong YS, Chen CF, Lee WH. Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J Biol Chem 1998; 273:6183–6189.

    Article  PubMed  CAS  Google Scholar 

  23. Taniguchi T, Tischkowitz M, Ameziane N, et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 2003; 9:568–574.

    Article  PubMed  CAS  Google Scholar 

  24. Durocher D, Jackson SP. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 2001; 13:225–231.

    Article  PubMed  CAS  Google Scholar 

  25. Tanaka T, Yamagami T, Oka Y, Nomura T, Sugiyama H. The scid mutation in mice causes defects in the repairsystemforbothdouble-strandDNA breaks and DNA cross-links. Mutat Res 1993; 288:277–280.

    PubMed  CAS  Google Scholar 

  26. Muller C, Calsou P, Salles B. The activity of the DNA-dependent protein kinase (DNA-PK) complex is determinant in the cellular response to nitrogen mustards. Biochimie 2000; 82:25–28.

    Article  PubMed  CAS  Google Scholar 

  27. Muller C, Christodoulopoulos G, Salles B, Panasci L. DNA-Dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood 1998; 92:2213–2219.

    PubMed  CAS  Google Scholar 

  28. Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 2001; 1:4129–4139.

    Article  Google Scholar 

  29. Guo Z, Kumagai A, Wang SX, Dunphy WG. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev 2000; 14:2745–2756.

    Article  PubMed  CAS  Google Scholar 

  30. Cliby WA, Roberts CJ, Cimprich KA, et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J 1998; 17:159–169.

    Article  PubMed  CAS  Google Scholar 

  31. Wright JA, Keegan KS, Herendeen DR, et al. Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc Natl AcadSciUSA 1998; 95:7445–7450.

    Article  CAS  Google Scholar 

  32. Andreassen PR, D’ Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 2004; 18:1958–1963.

    Article  PubMed  CAS  Google Scholar 

  33. Pichierri P, Rosselli F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. EMBO J 2004; 23:1178–1187.

    Article  PubMed  CAS  Google Scholar 

  34. Fan S, Chang JK, Smith ML, Duba D, Fornace AJ Jr, O’Connor PM. Cells lacking CIP1/WAF1 genes exhibit preferential sensitivity to cisplatin and nitrogen mustard. Oncogene 1997; 14:2127–2136.

    Article  PubMed  CAS  Google Scholar 

  35. Eymin B., Haugg M, Droin N, Sordet O, Dimanche-Boitrel MT, Solary E. p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells. Oncogene 1999; 18:1411–1418.

    Article  PubMed  CAS  Google Scholar 

  36. Ruan S, Okcu FM, Ren JP, et al. Overexpressed WAF1/CIP1 renders glioblastoma cells resistant to chemotherapy agents 1,3-bis-(2-chloroethyl)-1-nitrosurea and cisplatin. Cancer Res 1998; 58:1538–1543.

    PubMed  CAS  Google Scholar 

  37. Girard FU, Strausfeild A, Fernedez A, Lamb NJ. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 1991; 67:1169–1179.

    Article  PubMed  CAS  Google Scholar 

  38. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein required for the G1 to S phase transition. Mol Cell Biol 1995; 15:2612–2624.

    PubMed  CAS  Google Scholar 

  39. Mailand N, Falck J, Lukas C, et al. Rapid destruction of human Cdc25A in response to DNA damage. Science 2000; 288:1425–1429.

    Article  PubMed  CAS  Google Scholar 

  40. Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW. Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 2004; 23:2934–2949.

    Article  PubMed  CAS  Google Scholar 

  41. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626–629.

    Article  PubMed  CAS  Google Scholar 

  42. Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 2002; 9:505–512.

    Article  PubMed  CAS  Google Scholar 

  43. Harada H, Grant S. Apoptosis regulators. Rev Clin ExpHematol 2003; 7:117–138.

    CAS  Google Scholar 

  44. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15:1481–1486.

    Article  PubMed  CAS  Google Scholar 

  45. Reinhold WC, Kouros-Mehr H, Kohn KW, et al. Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling, functional analysis, and molecular interaction mapping. Cancer Res 2003; 63:1000–1011.

    PubMed  CAS  Google Scholar 

  46. Bellamy WT, Dalton WS, Gleason MC, Grogan TM, Trent JM. Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res 1991; 51:995–1002.

    PubMed  CAS  Google Scholar 

  47. Ahmad S, Okine L, Le B, Najarian P, Vistica DT. Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. J Biol Chem 1987; 262:15,048–15,053.

    PubMed  CAS  Google Scholar 

  48. Alaoui-Jamali MA, Panasci L, Centurioni GM, Schecter R, Lehnert S, Batist G. Nitrogen mustard-DNA interaction in melphalan-resistant mammary carcinoma cells with elevated intracellular glutathione and glutathione-S-transferase activity. Cancer Chemother Pharmacol 1992; 30:341–347.

    Article  PubMed  CAS  Google Scholar 

  49. Colvin OM, Friedman HS, Gamcsik MP, Fenselau C, Hilton J. Role of glutathione in cellular resistance to alkylating agents. Adv Enzyme Regul 1993; 33:19–26.

    Article  PubMed  CAS  Google Scholar 

  50. Ozols RF, O’Dwyer PJ, Hamilton TC, Young RC. The role of glutathione in drug resistance. Cancer Treat Rev 1990; 17(Suppl A): A45–A50.

    Article  Google Scholar 

  51. Suzukake K, Petro BJ, Vistica DT. Reduction in glutathione content of L-PAM resistant L1210 cells confers drug sensitivity. Biochem Pharmacol 1982; 31:121–124.

    Article  PubMed  CAS  Google Scholar 

  52. Somfai-Relle S, Suzukake K, Vistica BP, Vistica DT. Reduction in cellular glutathione by buthionine sulfoximine and sensitization of murine tumor cells resistant to L-phenylalanine mustard. Biochem Pharmacol 1984; 33:485–490.

    Article  PubMed  CAS  Google Scholar 

  53. Horton JK, Roy G, Piper JT, et al. Characterization of a chlorambucil-resistant human ovarian carcinoma cell line overexpressing glutathione S-transferase mu. Biochem Pharmacol 1999; 58:693–702.

    Article  PubMed  CAS  Google Scholar 

  54. Tipnis SR, Blake DG, Shepherd AG, McLellan LI. Overexpression of the regulatory subunit of ?-glutamylcysteine synthetase in HeLa cells increases ?-glutamylcysteine synthetase activity and confers drug resistance. Biochem J 1999; 337( Pt 3):559–566.

    Article  PubMed  CAS  Google Scholar 

  55. Nakagawa K, Saijo N, Tsuchida S, et al. Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines. J Biol Chem 1990; 265:4296–4301.

    PubMed  CAS  Google Scholar 

  56. Kondo Y, Woo ES, Michalska AE, Choo KH, Lazo JS. Metallothionein null cells have increased sensitivity to anticancer drugs. Cancer Res 1995; 55:2021–2023.

    PubMed  CAS  Google Scholar 

  57. Kelley SL, Basu A, Teicher B A, Hacker MP, Hamer DH, Lazo JS. Overexpression of metallothionein confers resistance to anticancer drugs. Science 1988; 241:1813–1815s.

    Article  PubMed  CAS  Google Scholar 

  58. Yu X, Wu Z, Fenselau C. Covalent sequestration of melphalan by metallothionein and selective alky-lation of cysteines. Biochemistry 1995; 34:3377–3385.

    Article  PubMed  CAS  Google Scholar 

  59. Barnouin K, Leier I, Jedlitschky G, et al. Multidrug resistance protein-mediated transport of chloram-bucil and melphalan conjugated to glutathione. Br J Cancer 1998; 77:201–209.

    PubMed  CAS  Google Scholar 

  60. Smitherman PK, Townsend AJ, Kute TE, Morrow CS. Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1-mediated resistance to chlorambucil cytotoxicity. J Pharmacol Exp Ther 2004; 308:260–267.

    Article  PubMed  CAS  Google Scholar 

  61. Yanagida O, Kanai Y, Chairoungdua A, et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 2001; 1514:291–302.

    Article  PubMed  CAS  Google Scholar 

  62. Nefedova Y, Landowski TH, Dalton WS. Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 2003; 17:1175–1182.

    Article  PubMed  CAS  Google Scholar 

  63. St. Croix B, Florenes VA, Rak JW, et al. Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nat Med 1996; 2:1204–1210.

    Article  PubMed  CAS  Google Scholar 

  64. Teicher BA, Holden SA, Ara G, Chen G. Transforming growth factor-β in in vivo resistance. Cancer Chemother Pharmacol 1996; 37:601–609.

    Article  PubMed  CAS  Google Scholar 

  65. Teicher B A, Ikebe M, Ara G, Keyes SR, Herbst RS. Transforming growth factor-β 1 overexpression produces drug resistance in vivo:revresal by decorin. In Vivo 1997; 11:463–472.

    PubMed  CAS  Google Scholar 

  66. Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin-CDK inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Devel 1994; 8:9–22.

    Article  PubMed  CAS  Google Scholar 

  67. Zhang Y, Lei XY. Effect of bcl-2 antisense oligodeoxynucleotides on drug sensitivity of leukemic cells. Hematol J 2003; 4:187–197.

    Article  PubMed  CAS  Google Scholar 

  68. Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992; 52:5407–5411.

    PubMed  CAS  Google Scholar 

  69. Minn AJ, Rudin CM, Boise LH, Thompson CB. Expression of bcl-xL can confer a multidrug resistance phenotype. Blood 1995; 86:1903–1910.

    PubMed  CAS  Google Scholar 

  70. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10:105–115.

    Article  PubMed  CAS  Google Scholar 

  71. Soma MR, Baetta R, De Renzis MR, et al. In vivo enhanced antitumor activity of carmustine [N,N’-bis-(2-chloroethyl)-N-nitrosourea] by simvastatin. Cancer Res 1995; 55:597–602.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

    Lori A. Hazlehurst PhD & William S. Dalton MD, PhD

Authors
  1. Lori A. Hazlehurst PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William S. Dalton MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Hazlehurst, L.A., Dalton, W.S. (2006). De Novo and Acquired Resistance to Antitumor Alkylating Agents. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_20

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-035-5_20

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-530-9

  • Online ISBN: 978-1-59745-035-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation