Skip to main content
PMC home page
Cytotechnology logoLink to Cytotechnology
. 1998 Sep;27(1-3):165–173. doi: 10.1023/A:1008060720608

Mechanisms of resistance to alkylating agents

G Damia 1, M D‘Incalci 1
PMCID: PMC3449574  PMID: 19002790

Abstract

Alkylating agents are the most widely used anticancer drugs whose main target is the DNA, although how exactly the DNA lesions cause cell death is still not clear. The emergence of resistance to this class of drugs as well as to other antitumor agents is one of the major causes of failure of cancer treatment. This paper reviews some of the best characterized mechanisms of resistance to alkylating agents. Pre- and post-target mechanisms are recognized, the former able to limit the formation of lethal DNA adducts, and the latter enabling the cell to repair or tolerate the damage. The role in the pre-target mechanisms of reduced drug accumulation and the increased detoxification or activation systems (such as DT-diaphorase, metallothionein, GST/GSH system, etc...) are discussed. In the post-target mechanisms the different DNA repair pathways, tolerance to alkylation damage and the ‘downstream’ effects (cell cycle arrest and/or apoptosis) are examined.

Keywords: alkylating agents, resistance

Full Text

The Full Text of this article is available as a PDF (62.2 KB).

Contributor Information

G. Damia, Email: deponcol@irfmn.mnegri.it

M. D‘Incalci, Email: deponcol@irfmn.mnegri.it

References

  1. Anthoney DA, McIlwrath AJ, Gallagher WM, Edlin AR, Brown R. Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells. Cancer Res. 1996;56:1374–1381. [PubMed] [Google Scholar]
  2. Armitage JO, Antman KH. High-dose cancer therapy: pharmacology, hematopoietins, stem cells. Ed. 2. Baltimore: Williams and Wilkins; 1995. [Google Scholar]
  3. Beith J, Hartley J, Darling J, Souhami R. DNA interstrand cross-linking and cytotoxicity induced by chloroethylnitrosoureas and cisplatin in human glioma cell lines which vary in cellular concentration of O6-alkylguanine-DNA alkyltransferase. Br J Cancer. 1997;75:500–505. doi: 10.1038/bjc.1997.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Belanich M, Pastor M, Randall T, Guerra D, Kibitel J, Alas L, Li B, Citron M, Wasserman P, White A, Eyre H, Jaeckle K, Schulman S, Rector D, Prados M, Coons S, Shapiro W, Yarosh D. Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res. 1996;56:783–788. [PubMed] [Google Scholar]
  5. Bodell WJ, Tokuda K, Ludlum DB. Differences in DNA alkylation products formed in sensitive and resistant human glioma cells treated with N-(2-chloroethyl)-N-nitrosourea. Cancer Res. 1988;48:4489–4492. [PubMed] [Google Scholar]
  6. Boise LH, Gonzalez Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74:597–608. doi: 10.1016/0092-8674(93)90508-N. [DOI] [PubMed] [Google Scholar]
  7. Bolton MG, Hilton J, Robertson KD, Streeper RT, Colvin OM, Noe DA. Kinetic analysis of the reaction of melphalan with water, phosphate, and glutathione. Drug Metab Dispos. 1993;21:986–996. [PubMed] [Google Scholar]
  8. Bramson J, O'Connor T. Effect of alkyl-Npurine DNA glycosylase overexpression on cellular resistance to bifunctional alkylating agents. Biochem Pharmacol. 1995;50:39–44. doi: 10.1016/0006-2952(95)00114-F. [DOI] [PubMed] [Google Scholar]
  9. Branch P, Aquilina G, Bignami M, Karran P. Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage. Nature. 1993;362:652–654. doi: 10.1038/362652a0. [DOI] [PubMed] [Google Scholar]
  10. Branch P, Hampson R, Karran P. DNA mismatch binding defects, DNA damage tolerance, and mutator phenotypes in human colorectal carcinoma cell lines. Cancer Res. 1995;55:2304–2309. [PubMed] [Google Scholar]
  11. Brown SJ, Kellett PJ, Lippard SJ. Ixr1, a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin. Science. 1993;261:603–605. doi: 10.1126/science.8342024. [DOI] [PubMed] [Google Scholar]
  12. Bruhn SL, Pil PM, Essigmann JM, Housman DE, Lippard SJ. Isolation and characterization of human cDNA clones encoding a high mobility group box protein that recognizes structural distortions to DNA caused by binding of the anticancer agent cisplatin. Proc Natl Acad Sci USA. 1992;89:2307–2311. doi: 10.1073/pnas.89.6.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bubley GJ, Ogata GK, Dupuis NP, Teicher BA. Detection of sequence-specific antitumor alkylating agent DNA damage from cells treated in culture and from a patient. Cancer Res. 1994;54:6325–6329. [PubMed] [Google Scholar]
  14. Bunting KD, Townsend AJ. Mafosfamide sensitivity in human MCF-7 breast carcinoma cell lines expressing transfected rat class 3 aldehyde dehydrogenase (‘tumor ALDH’) Proc Am Ass Cancer Res. 1993;34:270. [Google Scholar]
  15. Buser K, Joncourt F, Altermatt H-J. Breast cancer: Pretreatment drug resistance parameters (GSH-system, ATase, Pglycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristic. Ann Oncol. 1997;8:335–341. doi: 10.1023/A:1008202723066. [DOI] [PubMed] [Google Scholar]
  16. Chaney SG, Sancar A. DNA repair: enzymatic mechanisms and relevance to drug response. J Natl Cancer Inst. 1996;88:1346–1360. doi: 10.1093/jnci/88.19.1346. [DOI] [PubMed] [Google Scholar]
  17. Chao CC, Huang SL, Lee LY, Lin Chao S. Identification of inducible damage-recognition proteins that are overexpressed in HeLa cells resistant to cis-diamminedichloroplatinum (II) Biochem J. 1991;277:875–878. doi: 10.1042/bj2770875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chin JL, Banerjee D, Kadhim SA, Kontozoglou TE, Chauvin PJ, Cherian MG. Metallothionein in testicular germ cell tumors and drug resistance. Clinical correlation. Cancer. 1993;72:3029–3035. doi: 10.1002/1097-0142(19931115)72:10<3029::AID-CNCR2820721027>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  19. Chu G, Chang E. Cisplatin-resistant cells express increased levels of a factor that recognizes damaged DNA. Proc Natl Acad Sci USA. 1990;87:3324–3328. doi: 10.1073/pnas.87.9.3324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ciaccio PJ, Tew KD, LaCreta FP. Enzymatic conjugation of chlorambucil with glutathione by human glutathione S-transferases and inhibition by ethacrynic acid. Biochem Pharmacol. 1991;42:1504–1507. doi: 10.1016/0006-2952(91)90468-K. [DOI] [PubMed] [Google Scholar]
  21. Codegoni AM, Broggini M, Pitelli MR, Pantarotto M, Torri V, Mangioni G, D'Incalci M. Expression of genes of potential importance in the response to chemotherapy and DNA repair in patients with ovarian cancer. Gynecol Oncol. 1997;65:130–137. doi: 10.1006/gyno.1996.4609. [DOI] [PubMed] [Google Scholar]
  22. Colella G, Bonfanti M, D'Incalci M. Characterization of a protein recognizing minor groove bindersdamaged DNA. Nucleic Acids Res. 1996;24:4227–4233. doi: 10.1093/nar/24.21.4227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Cotter TG, Samali A. Oncogenes, apoptosis and cancer. FORUM. 1997;7:4–17. [Google Scholar]
  24. D'Incalci M and Sessa C (1997) DNA minor groove binding ligands: a new class of anticancer agents. Exp Opin Invest Drugs 6 (In Press). [DOI] [PubMed]
  25. Dabholkar M, Vionnet J, Bostick Bruton F, Yu JJ, Reed E. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest. 1994;94:703–708. doi: 10.1172/JCI117388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Damia G, Imperatori L, Citti L, Mariani L, D'Incalci M. 3-methyladenine-DNA-glycosylase and O6-alkyl guanine-DNA-lkyltransferase activities and sensitivity to alkylating agents in human cancer cell lines. Br J Cancer. 1996;73:861–865. doi: 10.1038/bjc.1996.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. De Feudis P, Debernardis D, Beccaglia P, Valenti M, Graniela Siré E, Azzani D, Stanzione S, Parodi S, D'Incalci M, Russo P and Broggini M (1997) DDP-induced cytotoxicity is not influenced by p53 in nine human ovarian cancer cell lines with different p53 status. Br J Cancer 76. [DOI] [PMC free article] [PubMed]
  28. De Vita VTJ, Hellman S, Rosemberg SA. Principles and practice of oncology. Ed. 5. Philadelphia: Lippincott-Raven; 1997. Cancer. [Google Scholar]
  29. Dirven HA, van Ommen B, van Bladeren PJ. Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res. 1994;54:6215–6220. [PubMed] [Google Scholar]
  30. Dole M, Nunez G, Merchant AK, Maybaum J, Rode CK, Bloch CA, Castle VP. Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res. 1994;54:3253–3259. [PubMed] [Google Scholar]
  31. Drummond JT, Anthoney A, Brown R, Modrich P. Cisplatin and adriamycin resistance are associated with MutLa and mismatch repair deficiency in an ovarian tumor cell line. J Biol Chem. 1996;271:19645–19648. doi: 10.1074/jbc.271.33.19645. [DOI] [PubMed] [Google Scholar]
  32. Eastman A. Characterization of the adducts produced in DNA by cis-diamminedichloroplatinum(II) and cisdichloro(ethylenediamine)platinum(II) Biochemistry. 1983;22:3927–3933. doi: 10.1021/bi00285a031. [DOI] [PubMed] [Google Scholar]
  33. Egyhazi S, Bergh J, Hansson J, Karran P, Ringborg U. Carmustine-induced toxicity, DNA crosslinking and O6-methylguanine-DNA methyltransferase activity in two human lung cancer cell lines. Eur J Cancer. 1991;27:1658–1662. doi: 10.1016/0277-5379(91)90440-O. [DOI] [PubMed] [Google Scholar]
  34. El-Deiry WS. p53, p21WAF1/CIP1 and the control of cell proliferation. In: Thomas NSB, editor. In Cell cycle control and apoptosis in malignant disease. Oxford: Bios Scientific Publishers; 1996. pp. 55–75. [Google Scholar]
  35. Eliopoulos AG, Kerr DJ, Herod J, Hodgkins L, Krajewski S, Reed JC, Young LS. The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene. 1995;11:1217–1228. [PubMed] [Google Scholar]
  36. Engelward BP, Dreslin A, Christensen J, Kurahara C, Samson L. Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have encreased sensitivity to alkylation-induced chromosome damage and cell killing. EMBO J. 1996;15:945–952. [PMC free article] [PubMed] [Google Scholar]
  37. Fan S, Smith ML, Rivet DJ, Duba D, Zhan Q, Kohn KW, Fornace AJ, Jr, O'Connor PM. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res. 1995;55:1649–1654. [PubMed] [Google Scholar]
  38. Ferrandina G, Scambia G, Damia G. Glutathione Stransferase activity in epithelial ovarian cancer: Association with response to chemotherapy and disease outcome. Ann Oncol. 1997;8:343–350. doi: 10.1023/A:1008247428385. [DOI] [PubMed] [Google Scholar]
  39. Ferrando AA, Velasco G, Campo E, Lopez Otin C. Cloning and expression analysis of human bleomycin hydrolase, a cysteine proteinase involved in chemotherapy resistance. Cancer Res. 1996;56:1746–1750. [PubMed] [Google Scholar]
  40. Fitzsimmons SA, Workman P, Grever M, Paull K, Camalier R, Lewis AD. Reductase enzyme expression across the National Cancer Institute Tumor cell line panel: correlation with sensitivity to mitomycin C and EO9. J Natl Cancer Inst. 1996;88:259–269. doi: 10.1093/jnci/88.5.259. [DOI] [PubMed] [Google Scholar]
  41. Gibbons GR, Kaufmann WK, Chaney SG. Role of DNA replication in carrier-ligand-specific resistance to platinum compounds in L1210 cells. Carcinogenesis. 1991;12:2253–2257. doi: 10.1093/carcin/12.12.2253. [DOI] [PubMed] [Google Scholar]
  42. Gottlieb TM, Oren M. p53 in growth control and neoplasia. Biochim Biophys Acta. 1996;1287:77–102. doi: 10.1016/0304-419x(95)00019-c. [DOI] [PubMed] [Google Scholar]
  43. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–4878. [PubMed] [Google Scholar]
  44. Hannun YA. Apoptosis dilemma of cancer chemotherapy. Blood. 1997;89:1845–1853. [PubMed] [Google Scholar]
  45. Hemminki K and Kallama S (1986) Reactions of nitrogen mustards with DNA. IARC Sci Publ 55-70. [PubMed]
  46. Hemminki K (1994) DNA adducts of nitrogen mustards and ethylene imines. IARC Sci Publ 313-321. [PubMed]
  47. Hill BT, Shellard SA, Fichtinger Schepman AM, Schmoll HJ, Harstrick A. Differential formation and enhanced removal of specific cisplatin-DNA adducts in two cisplatin-selected resistant human testicular teratoma sublines. Anticancer Drugs. 1994;5:321–328. doi: 10.1097/00001813-199406000-00010. [DOI] [PubMed] [Google Scholar]
  48. Hilton J. Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. Cancer Res. 1984;44:5156–5160. [PubMed] [Google Scholar]
  49. Hockenbery D, Nunez G, illiman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348:334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  50. Hotta T, Saito Y, Fujita H, Mikami T, Kurisu K, Kiya K, Uozumi T, Isowa G, Ishizaki K, Ikenaga M. O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. J Neurooncol. 1994;21:135–140. doi: 10.1007/BF01052897. [DOI] [PubMed] [Google Scholar]
  51. Huang JC, Zamble DB, Reardon JT, Lippard SJ, Sancar A. HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc Natl Acad Sci USA. 1994;91:10394–10398. doi: 10.1073/pnas.91.22.10394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hurley LH, Reynolds VL, Swenson DH, Petzold GL, Scahill TA. Reaction of the antitumor antibiotic CC-1065 with DNA: structure of a DNA adduct with DNA sequence specificity. Science. 1984;226:843–844. doi: 10.1126/science.6494915. [DOI] [PubMed] [Google Scholar]
  53. Johnson SW, Shen D, Pastan I, Gottesman MM, Hamilton TC. Cross-resistance, cisplatin accumulation, and platinum-DNA adduct formation and removal in cisplatin-sensitive and-resistant human hepatoma cell lines. Exp Cell Res. 1996;226:133–139. doi: 10.1006/excr.1996.0211. [DOI] [PubMed] [Google Scholar]
  54. Karran P, Bignami M. DNA damage tolerance, mismatch repair and genome instability. Bioessays. 1994;16:833–839. doi: 10.1002/bies.950161110. [DOI] [PubMed] [Google Scholar]
  55. Kat A, Thilly WG, Fang WH, Longley MJ, Li GM, Modrich P. An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci USA. 1993;90:6424–6428. doi: 10.1073/pnas.90.14.6424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Kaufmann WK. Pathways of human cell post-replication repair. Carcinogenesis. 1989;10:1–11. doi: 10.1093/carcin/10.1.1. [DOI] [PubMed] [Google Scholar]
  57. Kelley SL, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS. Overexpression of metallothionein confers resistance to anticancer drugs. Science. 1988;241:1813–1815. doi: 10.1126/science.3175622. [DOI] [PubMed] [Google Scholar]
  58. Kondo S, Barnett GH, Hara H, Morimura T, Takeuchi J. MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. Oncogene. 1995;10:2001–2006. [PubMed] [Google Scholar]
  59. Lasorella A, Iavarone A, Israel MA. Differentiation of neuroblastoma enhances Bcl-2 expression and induces alterations of apoptosis and drug resistance. Cancer Res. 1995;55:4711–4716. [PubMed] [Google Scholar]
  60. Lohrer H, Robson T. Overexpression of metallothionein in CHO cells and its effect on cell killing by ionizing radiation and alkylating agents. Carcinogenesis. 1989;10:2279–2284. doi: 10.1093/carcin/10.12.2279. [DOI] [PubMed] [Google Scholar]
  61. Mamenta EL, Poma EE, Kaufmann WK, Delmastro DA, Grady HL, Chaney SG. Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res. 1994;54:3500–3505. [PubMed] [Google Scholar]
  62. McA'Nulty MM and Lippard SJ (1996) The HMG-domain protein Ixr1 blocks excision repair of cisplatin-DNA adducts in yeast. Mutat Res 362: 75-86. [DOI] [PubMed]
  63. McDonald ER, Wu GS, Waldman T, El Deiry WS. Repair Defect in p21WAF1/CIP1-/-human cancer cells. Cancer Res. 1996;56:2250–2255. [PubMed] [Google Scholar]
  64. Minn AJ, Rudin CM, Boise LH, Thompson CB. Expression of bcl-xL can confer a multidrug resistance phenotype. Blood. 1995;86:1903–1910. [PubMed] [Google Scholar]
  65. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101–133. doi: 10.1146/annurev.bi.65.070196.000533. [DOI] [PubMed] [Google Scholar]
  66. Moscow JA, Swanson CA, Cowan KH. Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. Br J Cancer. 1993;68:732–737. doi: 10.1038/bjc.1993.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Mu D, Park CH, Matsunaga T, Hsu DS, Reardon JT, Sancar A. Reconstitution of human DNA repair excision nuclease in a highly defined system. J Biol Chem. 1995;270:2415–2418. doi: 10.1074/jbc.270.6.2415. [DOI] [PubMed] [Google Scholar]
  68. Nichols AF, Schmidt WJ, Chaney SG, Sancar A. Limitations of the in vitro repair synthesis assay for probing the role of DNA repair in platinum resistance. Chem Biol Interact. 1992;81:223–231. doi: 10.1016/0009-2797(92)90079-Z. [DOI] [PubMed] [Google Scholar]
  69. Niimi S, Nakagawa K, Yokota J, Tsunokawa Y, Nishio K, Terashima Y, Shibuya M, Terada M, Saijo N. Resistance to anticancer drugs in NIH3T3 cells transfected with c-myc and/or c-H-ras genes. Br J Cancer. 1991;63:237–241. doi: 10.1038/bjc.1991.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Panasci L, Henderson D, Torres Garcia SJ, Skalski V, Caplan S, Hutchinson M. Transport, metabolism, and DNA interaction of melphalan in lymphocytes from patients with chronic lymphocytic leukemia. Cancer Res. 1988;48:1972–1976. [PubMed] [Google Scholar]
  71. Perego P, Giarola M, Righetti SC, Supino R, Caserini C, Delia D, Pierotti MA, Miyashita T, Reed JC, Zunino F. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 1996;56:556–562. [PubMed] [Google Scholar]
  72. Povirk LF, Shuker DE. DNA damage and mutagenesis induced by nitrogen mustards. Mutat Res. 1994;318:205–226. doi: 10.1016/0165-1110(94)90015-9. [DOI] [PubMed] [Google Scholar]
  73. Ryan JJ, Danish R, Gottlieb CA, Clarke MF. Cell cycle analysis of p53-induced cell death in murine erythroleukemia cells. Mol Cell Biol. 1993;13:711–719. doi: 10.1128/mcb.13.1.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J. Induction of apoptosis by wild-type p53 in a human colon tumorderived cell line. Proc Natl Acad Sci USA. 1992;89:4495–4499. doi: 10.1073/pnas.89.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Sklar MD, Prochownik EV. Modulation of cis-platinum resistance in Friend erythroleukemia cells by c-myc. Cancer Res. 1991;51:2118–2123. [PubMed] [Google Scholar]
  76. Sladek NE, Landkamer GJ. Restoration of sensitivity to oxazaphosphorines by inhibitors of aldehyde dehydrogenase activity in cultured oxazaphosphorine-resistant L1210 and cross-linking agent-resistant P388 cell lines. Cancer Res. 1985;45:1549–1555. [PubMed] [Google Scholar]
  77. Sreerama L, Sladek NE. Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. Biochem Pharmacol. 1993;45:2487–2505. doi: 10.1016/0006-2952(93)90231-K. [DOI] [PubMed] [Google Scholar]
  78. Strandberg MC, Bresnick E, Eastman A. The significance of DNA cross-linking to cis-diamminedichloroplatinum(II)-induced cytotoxicity in sensitive and resistant lines of murine leukemia L1210 cells. Chem Biol Interact. 1982;39:169–180. doi: 10.1016/0009-2797(82)90119-3. [DOI] [PubMed] [Google Scholar]
  79. Sumantran VN, Ealovega MW, Nunez G, Clarke MF, Wicha MS. Overexpression of Bcl-XS sensitizes MCF-7 cells to chemotherapy-induced apoptosis. Cancer Res. 1995;55:2507–2510. [PubMed] [Google Scholar]
  80. Tew KD, Bomber AM, Hoffman SJ. Ethacrynic acid and piriprost as enhancers of cytotoxicity in drug resistant and sensitive cell lines. Cancer Res. 1988;48:3622–3625. [PubMed] [Google Scholar]
  81. Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res. 1994;54:4313–4320. [PubMed] [Google Scholar]
  82. Torres Garcia SJ, Cousineau L, Caplan S, Panasci L. Correlation of resistance to nitrogen mustards in chronic lymphocytic leukemia with enhanced removal of melphalan-induced DNA cross-links. Biochem Pharmacol. 1989;38:3122–3123. doi: 10.1016/0006-2952(89)90025-7. [DOI] [PubMed] [Google Scholar]
  83. Tsuchida S, Sato K. Glutathione transferases and cancer. Crit Rev Biochem Mol Biol. 1992;27:337–384. doi: 10.3109/10409239209082566. [DOI] [PubMed] [Google Scholar]
  84. Vaisman A, Chaney SG. Induction of UV-damage recognition protein by cisplatin treatment. Biochemistry. 1995;34:105–114. doi: 10.1021/bi00001a013. [DOI] [PubMed] [Google Scholar]
  85. Waldman T, Lengauer C, Kinzler KW, Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 (see comments) Nature. 1996;381:713–716. doi: 10.1038/381713a0. [DOI] [PubMed] [Google Scholar]
  86. Waxman DJ. Glutathione S-transferases: role in alkylating agent resistance and possible target for modulation chemotherapy-a review. Cancer Res. 1990;50:6449–6454. [PubMed] [Google Scholar]
  87. Wu ZN, Chan CL, Eastman A, Bresnick E. Expression of human O6-methylguanine-DNA methyltransferase in a DNA excision repair-deficient Chinese hamster ovary cell line and its response to certain alkylating agents. Cancer Res. 1992;52:32–35. [PubMed] [Google Scholar]
  88. Yarosh DB, Barnes D, Erickson LC. Transfection of DNA from a chloroethylnitrosourea-resistant tumor cell line (MER+) to a sensitive tumor cell line (MER-) results in a tumor cell line resistant to MNNG and CNU that has increased O-6-methylguanine-DNA methyltransferase levels and reduced levels of DNA interstrand crosslinking. Carcinogenesis. 1986;7:1603–1606. doi: 10.1093/carcin/7.9.1603. [DOI] [PubMed] [Google Scholar]
  89. Yonish Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991;352:345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]
  90. Yu JJ, Dabholkar M, Bennett WP, Welsh JA, Mu CJB-B. Platinum-sensitive and platinum-resistant ovarian cancer tissue show differences in the relationships between mRNA levels of p53, ERCC1 and XPA. Int J Oncol. 1996;8:313–317. doi: 10.3892/ijo.8.2.313. [DOI] [PubMed] [Google Scholar]
  91. Zwelling LA, Anderson T, Kohn KW. DNA-protein and DNA interstrand cross-linking by cis-and trans-platinum(II) diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity. Cancer Res. 1979;39:365–369. [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES