Source: http://www.asmscience.org/content/book/10.1128/9781555817572.chap36
Timestamp: 2019-04-25 10:29:11+00:00

Document:
Drug resistance, either intrinsic or acquired, remains one of the primary causes of failure for cancer chemotherapy. This chapter focuses on alterations in the carrier mediated transport systems that are responsible for intrinsic and acquired resistance. As with the antifolate drugs, a single, or a combination of different, mechanism(s) can mediate resistance to nucleoside anticancer agents. Reduced cellular accumulation of anticancer agents is one of the most studied forms of multidrug resistance (MDR). In terms of cellular resistance to anticancer agents, at least 10 family members have been implicated in drug resistance (MRP1-7, MDR1, BCRP, and ABCA2), and four of these have been shown to generate a resistance phenotype in cultured cells. Resistance to several different anticancer agents that are substrates for glutathione-S-transferase (GST) is associated with increases in GST levels (e.g., chlorambucil, melphalan). Interestingly, increased GST levels have been shown to be associated with resistance to non-GST-substrate anticancer agents. Commonly used camptothecins include topotecan and irinotecan. Cell culture based experiments have elucidated several point mutations in the TopoI enzyme, which are responsible for resistance. It should be noted that mutations in TopoI produce resistance to a class of molecules but do not always grant cross-resistance to other TopoI inhibitors. A better understanding of the mechanisms operating at the clinical level is crucial for the development of drugs aimed at circumventing resistance or therapeutic regimens for preventing the emergence of resistance.
Overview of the basic mechanisms of resistance.
Chemical structure of folic acid (folate), a naturally occurring vitamin necessary for cells, presented opposite the anticancer drug methotrexate.
Chemical structures for clinically used nucleoside drugs.
Mutations in the topoisomerase I gene that result in increased resistance to drug.
Topoisomerase II mutations that result in increased drug resistance.
1. Abbruzzese, J. L.,, R. Grunewald,, E. A. Weeks,, D. Gravel,, T. Adams,, B. Nowak,, S. Mineishi,, P. Tarassoff,, W. Satterlee,, and M. N. Raber. 1991. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J. Clin. Oncol. 9: 491– 498.
2. Adler, V.,, Z. Yin,, S. Y. Fuchs,, M. Benezra,, L. Rosario,, K. D. Tew,, M. R. Pincus,, M. Sardana,, C. J. Henderson,, C. R. Wolf,, R. J. Davis,, and Z. Ronai. 1999. Regulation of JNK signaling by GSTp. EMBO J. 18: 1321– 1334.
3. Aebersold, D. M.,, A. Kollar,, K. T. Beer,, J. Laissue,, R. H. Greiner,, and V. Djonov. 2001. Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation. Int. J. Cancer 96: 41– 54.
4. Agrawal, M.,, J. Abraham,, F. M. Balis,, M. Edgerly,, W. D. Stein,, S. Bates,, T. Fojo,, and C. C. Chen. 2003. Increased 99mTc-sestamibi accumulation in normal liver and drugresistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin. Cancer Res. 9: 650– 656.
5. Ambudkar, S. V.,, S. Dey,, C. A. Hrycyna,, M. Ramachandra,, I. Pastan,, and M. M. Gottesman. 1999. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39: 361– 398.
6. Ambudkar, S. V.,, C. Kimchi-Sarfaty,, Z. E. Sauna,, and M. M. Gottesman. 2003. P-glycoprotein: from genomics to mechanism. Oncogene 22: 7468– 7485.
7. Ambudkar, S. V.,, I. H. Lelong,, J. Zhang,, C. O. Cardarelli,, M. M. Gottesman,, and I. Pastan. 1992. Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. Proc. Natl. Acad. Sci. USA 89: 8472– 8476.
8. Armitage, J. O.,, K. Tobinai,, D. Hoelzer,, and M. J. Rummel. 2004. Treatment of indolent non-Hodgkin’s lymphoma with cladribine as single-agent therapy and in combination with mitoxantrone. Int. J. Hematol. 79: 311– 321.
9. Aschele, C.,, D. Debernardis,, S. Casazza,, G. Antonelli,, G. Tunesi,, C. Baldo,, R. Lionetto,, F. Maley,, and A. Sobrero. 1999. Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J. Clin. Oncol. 17: 1760– 1770.
10. Bain, L. J.,, J. B. McLachlan,, and G. A. LeBlanc. 1997. Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein. Environ. Health Perspect. 105: 812– 818.
11. Bairey, O.,, Y. Zimra,, M. Shaklai,, E. Okon,, and E. Rabizadeh. 1999. Bcl-2, Bcl-X, Bax, and Bak expression in short- and long-lived patients with diffuse large B-cell lymphomas. Clin. Cancer Res. 5: 2860– 2866.
12. Bakos, E.,, R. Evers,, G. Szakacs,, G. E. Tusnady,, E. Welker,, K. Szabo,, M. de Haas,, L. van Deemter,, P. Borst,, A. Varadi,, and B. Sarkadi. 1998. Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J. Biol. Chem. 273: 32167– 32175.
13. Baldwin, S. A.,, J. R. Mackey,, C. E. Cass,, and J. D. Young. 1999. Nucleoside transporters: molecular biology and implications for therapeutic development. Mol. Med. Today 5: 216– 224.
14. Barbour, K. W.,, D. K. Hoganson,, S. H. Berger,, and F. G. Berger. 1992. A naturally occurring tyrosine to histidine replacement at residue 33 of human thymidylate synthase confers resistance to 5-fluoro-2′-deoxyuridine in mammalian and bacterial cells. Mol. Pharmacol. 42: 242– 248.
15. Barrueco, J. R.,, D. F. O’Leary,, and F. M. Sirotnak. 1992. Facilitated transport of methotrexate polyglutamates into lysosomes derived from S180 cells. Further characterization and evidence for a simple mobile carrier system with broad specificity for homo- or heteropeptides bearing a C-terminal glutamyl moiety. J. Biol. Chem. 267: 19986– 19991.
16. Baugh, C. M.,, and C. L. Krumdieck. 1971. Naturally occurring folates. Ann. N. Y. Acad. Sci. 186: 7– 28.
17. Baugh, C. M.,, C. L. Krumdieck,, and M. G. Nair. 1973. Polygammaglutamyl metabolites of methotrexate. Biochem. Biophys. Res. Commun. 52: 27– 34.
18. Beck, W. T.,, M. K. Danks,, J. S. Wolverton,, M. Chen,, B. Granzen,, R. Kim,, and D. P. Suttle. 1994. Resistance of mammalian tumor cells to inhibitors of DNA topoisomerase II. Adv. Pharmacol. 29B: 145– 169.
19. Belinsky, M. G.,, and G. D. Kruh. 1999. MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver. Br. J. Cancer 80: 1342– 1349.
20. Belt, J. A.,, N. M. Marina,, D. A. Phelps,, and C. R. Crawford. 1993. Nucleoside transport in normal and neoplastic cells. Adv. Enzyme Regul. 33: 235– 252.
21. Bergen, A. A.,, A. S. Plomp,, E. J. Schuurman,, S. Terry,, M. Breuning,, H. Dauwerse,, J. Swart,, M. Kool,, S. van Soest,, F. Baas,, J. B. ten Brink,, and P. T. de Jong. 2000. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat. Genet. 25: 228– 231.
22. Bharti, A. K.,, M. O. Olson,, D. W. Kufe,, and E. H. Rubin. 1996. Identification of a nucleolin binding site in human topoisomerase I. J. Biol. Chem. 271: 1993– 1997.
23. Blagosklonny, M. V.,, P. Giannakakou,, M. Wojtowicz,, L. Y. Romanova,, K. B. Ain,, S. E. Bates,, and T. Fojo. 1998. Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. J. Clin. Endocrinol. Metab. 83: 2516– 2522.
24. Blakley, R. L.,, and S. J. Benkovic. 1984. Folates and pterins, vol. v.1. Wiley, New York, N.Y.
25. Bleicher, R. J.,, and M. C. Cabot. 2002. Glucosylceramide synthase and apoptosis. Biochim. Biophys. Acta 1585: 172– 178.
26. Bohme, M.,, G. Jedlitschky,, I. Leier,, M. Buchler,, and D. Keppler. 1994. ATP-dependent export pumps and their inhibition by cyclosporins. Adv. Enzyme Regul. 34: 371– 380.
27. Borst, P.,, and R. O. Elferink. 2002. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71: 537– 592.
28. Borst, P.,, R. Evers,, M. Kool,, and J. Wijnholds. 2000. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 92: 1295– 1302.
29. Borst, P.,, R. Evers,, M. Kool,, and J. Wijnholds. 1999. The multidrug resistance protein family. Biochim. Biophys. Acta 1461: 347– 357.
30. Borst, P.,, N. Zelcer,, and A. van Helvoort. 2000. ABC transporters in lipid transport. Biochim. Biophys. Acta 1486: 128– 144.
31. Boyer, J.,, E. G. McLean,, S. Aroori,, P. Wilson,, A. McCulla,, P. D. Carey,, D. B. Longley,, and P. G. Johnston. 2004. Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. Clin. Cancer Res. 10: 2158– 2167.
32. Bradshaw, D. M.,, and R. J. Arceci. 1998. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J. Clin. Oncol. 16: 3674– 3690.
33. Brangi, M.,, T. Litman,, M. Ciotti,, K. Nishiyama,, G. Kohlhagen,, C. Takimoto,, R. Robey,, Y. Pommier,, T. Fojo,, and S. E. Bates. 1999. Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 59: 5938– 5946.
34. Brigle, K. E.,, M. J. Spinella,, E. E. Sierra,, and I. D. Goldman. 1995. Characterization of a mutation in the reduced folate carrier in a transport defective L1210 murine leukemia cell line. J. Biol. Chem. 270: 22974– 22979.
35. Buckwalter, C. A.,, A. H. Lin,, A. Tanizawa,, Y. G. Pommier,, Y. C. Cheng,, and S. H. Kaufmann. 1996. RNA synthesis inhibitors alter the subnuclear distribution of DNA topoisomerase I. Cancer Res. 56: 1674– 1681.
36. Campbell, L. J.,, C. Patsouris,, K. C. Rayeroux,, K. Somana,, E. H. Januszewicz,, and J. Szer. 2002. BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet. Cytogenet. 139: 30– 33.
37. Capiaux, G. M.,, T. Budak-Alpdogan,, N. Takebe,, P. Mayer- Kuckuk,, D. Banerjee,, F. Maley,, and J. R. Bertino. 2003. Retroviral transduction of a mutant dihydrofolate reductasethymidylate synthase fusion gene into murine marrow cells confers resistance to both methotrexate and 5-fluorouracil. Hum. Gene Ther. 14: 435– 446.
38. Caponigro, F.,, M. Casale,, and J. Bryce. 2003. Farnesyl transferase inhibitors in clinical development. Expert Opin. Investig. Drugs 12: 943– 954.
39. Carman, M. D.,, J. H. Schornagel,, R. S. Rivest,, S. Srimatkandada,, C. S. Portlock,, T. Duffy,, and J. R. Bertino. 1984. Resistance to methotrexate due to gene amplification in a patient with acute leukemia. J. Clin. Oncol. 2: 16– 20.
40. Champoux, J. J. 2001. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 70: 369– 413.
41. Chang, G. 2003. Multidrug resistance ABC transporters. FEBS Lett. 555: 102– 105.
42. Chang, G.,, and C. B. Roth. 2001. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 293: 1793– 1800.
43. Chazal, M.,, S. Cheradame,, J. L. Formento,, M. Francoual,, P. Formento,, M. C. Etienne,, E. Francois,, H. Richelme,, M. Mousseau,, C. Letoublon,, D. Pezet,, H. Cure,, J. F. Seitz,, and G. Milano. 1997. Decreased folylpolyglutamate synthetase activity in tumors resistant to fluorouracil-folinic acid treatment: clinical data. Clin. Cancer Res. 3: 553– 557.
44. Chen, C. J.,, J. E. Chin,, K. Ueda,, D. P. Clark,, I. Pastan,, M. M. Gottesman,, and I. B. Roninson. 1986. Internal duplication and homology with bacterial transport proteins in the mdr1 (Pglycoprotein) gene from multidrug-resistant human cells. Cell 47: 381– 389.
45. Chen, Z. S.,, K. Lee,, and G. D. Kruh. 2001. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J. Biol. Chem. 276: 33747– 33754.
46. Cheng, E. H.,, M. C. Wei,, S. Weiler,, R. A. Flavell,, T. W. Mak,, T. Lindsten,, and S. J. Korsmeyer. 2001. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell. 8: 705– 711.
47. Childs, S.,, R. L. Yeh,, D. Hui,, and V. Ling. 1998. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein. Cancer Res. 58: 4160– 4167.
48. Chrencik, J. E.,, B. L. Staker,, A. B. Burgin,, P. Pourquier,, Y. Pommier,, L. Stewart,, and M. R. Redinbo. 2004. Mechanisms of camptothecin resistance by human topoisomerase I mutations. J. Mol. Biol. 339: 773– 784.
49. Cole, S. P.,, G. Bhardwaj,, J. H. Gerlach,, J. E. Mackie,, C. E. Grant,, K. C. Almquist,, A. J. Stewart,, E. U. Kurz,, A. M. Duncan,, and R. G. Deeley. 1992. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258: 1650– 1654.
50. Cole, S. P.,, and R. G. Deeley. 1993. Multidrug resistanceassociated protein: sequence correction. Science 260: 879.
51. Colly, L. P.,, W. G. Peters,, D. Richel,, M. W. Arentsen-Honders,, C. W. Starrenburg,, and R. Willemze. 1987. Deoxycytidine kinase and deoxycytidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia. Semin. Oncol. 14: 257– 261.
52. Cordon-Cardo, C.,, J. P. O’Brien,, J. Boccia,, D. Casals,, J. R. Bertino,, and M. R. Melamed. 1990. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38: 1277– 1287.
53. Cory, J. G.,, and A. Sato. 1983. Regulation of ribonucleotide reductase activity in mammalian cells. Mol. Cell Biochem. 53– 54: 257– 266.
54. Cragg, G. M.,, and D. J. Newman. 2004. A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy. J. Nat. Prod. 67: 232– 244.
55. Crommentuyn, K. M.,, J. H. Schellens,, J. D. van den Berg,, and J. H. Beijnen. 1998. In-vitro metabolism of anti-cancer drugs, methods and applications: paclitaxel, docetaxel, tamoxifen and ifosfamide. Cancer Treat. Rev. 24: 345– 366.
56. Cummings, J.,, B. T. Ethell,, L. Jardine,, G. Boyd,, J. S. Macpherson,, B. Burchell,, J. F. Smyth,, and D. I. Jodrell. 2003. Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. Cancer Res. 63: 8443– 8450.
57. Cunningham, D. 1998. Mature results from three large controlled studies with raltitrexed (‘Tomudex’). Br. J. Cancer 77(Suppl 2): 15– 21.
58. Curt, G. A.,, D. N. Carney,, K. H. Cowan,, J. Jolivet,, B. D. Bailey,, J. C. Drake,, K. S. Chien Song,, J. D. Minna,, and B. A. Chabner. 1983. Unstable methotrexate resistance in human small-cell carcinoma associated with double minute chromosomes. N. Engl. J. Med. 308: 199– 202.
59. Curt, G. A.,, J. Jolivet,, D. N. Carney,, B. D. Bailey,, J. C. Drake,, N. J. Clendeninn,, and B. A. Chabner. 1985. Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate. J. Clin. Invest. 76: 1323– 1329.
60. Daley, G. Q.,, R. A. Van Etten,, and D. Baltimore. 1990. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247: 824– 830.
61. Danks, M. K.,, K. E. Garrett,, R. C. Marion,, and D. O. Whipple. 1996. Subcellular redistribution of DNA topoisomerase I in anaplastic astrocytoma cells treated with topotecan. Cancer Res. 56: 1664– 1673.
62. Danks, M. K.,, M. R. Warmoth,, E. Friche,, B. Granzen,, B. Y. Bugg,, W. G. Harker,, L. A. Zwelling,, B. W. Futscher,, D. P. Suttle,, and W. T. Beck. 1993. Single-strand conformational polymorphism analysis of the M(r) 170,000 isozyme of DNA topoisomerase II in human tumor cells. Cancer Res. 53: 1373– 1379.
63. Dean, M.,, A. Rzhetsky,, and R. Allikmets. 2001. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11: 1156– 1166.
64. Desai, A.,, and T. J. Mitchison. 1997. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13: 83– 117.
65. Dicker, A. P.,, M. Volkenandt,, B. I. Schweitzer,, D. Banerjee,, and J. R. Bertino. 1990. Identification and characterization of a mutation in the dihydrofolate reductase gene from the methotrexate-resistant Chinese hamster ovary cell line Pro-3 MtxRIII. J. Biol. Chem. 265: 8317– 8321.
66. Dicker, A. P.,, M. C. Waltham,, M. Volkenandt,, B. I. Schweitzer,, G. M. Otter,, F. A. Schmid,, F. M. Sirotnak,, and J. R. Bertino. 1993. Methotrexate resistance in an in vivo mouse tumor due to a non-active-site dihydrofolate reductase mutation. Proc. Natl. Acad. Sci. USA 90: 11797– 11801.
67. Dolnick, B. J.,, R. J. Berenson,, J. R. Bertino,, R. J. Kaufman,, J. H. Nunberg,, and R. T. Schimke. 1979. Correlation of dihydrofolate reductase elevation with gene amplification in a homogeneously staining chromosomal region in L5178Y cells. J. Cell Biol. 83: 394– 402.
68. Drake, J. C.,, C. J. Allegra,, R. G. Moran,, and P. G. Johnston. 1996. Resistance to tomudex (ZD1694): multifactorial in human breast and colon carcinoma cell lines. Biochem. Pharmacol. 51: 1349– 1355.
69. Draper, M. P.,, R. L. Martell,, and S. B. Levy. 1997. Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein. Br. J. Cancer 75: 810– 815.
70. Drori, S.,, G. Jansen,, R. Mauritz,, G. J. Peters,, and Y. G. Assaraf. 2000. Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. J. Biol. Chem. 275: 30855– 30863.
71. Drori, S.,, H. Sprecher,, G. Shemer,, G. Jansen,, I. D. Goldman,, and Y. G. Assaraf. 2000. Characterization of a human alternatively spliced truncated reduced folate carrier increasing folate accumulation in parental leukemia cells. Eur. J. Biochem. 267: 690– 702.
72. Druker, B. J. 2003. Imatinib alone and in combination for chronic myeloid leukemia. Semin. Hematol. 40: 50– 58.
73. Duckett, C. S.,, V. E. Nava,, R. W. Gedrich,, R. J. Clem,, J. L. Van Dongen,, M. C. Gilfillan,, H. Shiels,, J. M. Hardwick,, and C. B. Thompson. 1996. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J. 15: 2685– 2694.
74. Duffy, C. P.,, C. J. Elliott,, R. A. O’Connor,, M. M. Heenan,, S. Coyle,, I. M. Cleary,, K. Kavanagh,, S. Verhaegen,, C. M. O’Loughlin,, R. NicAmhlaoibh,, and M. Clynes. 1998. Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal antiinflammatory drugs (NSAIDs). Eur. J. Cancer 34: 1250– 1259.
75. Ecker, G.,, M. Huber,, D. Schmid,, and P. Chiba. 1999. The importance of a nitrogen atom in modulators of multidrug resistance. Mol. Pharmacol. 56: 791– 796.
76. Edwards, T. K.,, A. Saleem,, J. A. Shaman,, T. Dennis,, C. Gerigk,, E. Oliveros,, M. R. Gartenberg,, and E. H. Rubin. 2000. Role for nucleolin/Nsr1 in the cellular localization of topoisomerase I. J. Biol. Chem. 275: 36181– 36188.
77. Ejendal, K. F.,, and C. A. Hrycyna. 2002. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr. Protein Pept. Sci. 3: 503– 511.
78. El-Deiry, W. S. 2003. The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22: 7486– 7495.
79. Eng, W. K.,, F. L. McCabe,, K. B. Tan,, M. R. Mattern,, G. A. Hofmann,, R. D. Woessner,, R. P. Hertzberg,, and R. K. Johnson. 1990. Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content. Mol. Pharmacol. 38: 471– 480.
80. Etienne, M. C.,, T. Guillot,, and G. Milano. 1996. Critical factors for optimizing the 5-fluorouracil-folinic acid association in cancer chemotherapy. Ann. Oncol. 7: 283– 289.
81. Evans, C. D.,, S. E. Mirski,, M. K. Danks,, and S. P. Cole. 1994. Reduced levels of topoisomerase II alpha and II beta in a multidrug-resistant lung-cancer cell line. Cancer Chemother. Pharmacol. 34: 242– 248.
82. Evans, W. E.,, and M. V. Relling. 1999. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286: 487– 491.
83. Evers, R.,, M. de Haas,, R. Sparidans,, J. Beijnen,, P. R. Wielinga,, J. Lankelma,, and P. Borst. 2000. Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br. J. Cancer 83: 375– 383.
84. Evers, R.,, M. Kool,, A. J. Smith,, L. van Deemter,, M. de Haas,, and P. Borst. 2000. Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1-and MRP2-mediated transport. Br. J. Cancer 83: 366– 374.
85. Fabre, I.,, G. Fabre,, and I. D. Goldman. 1984. Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro. Cancer Res. 44: 3190– 3195.
86. Fan, Y.,, J. N. Weinstein,, K. W. Kohn,, L. M. Shi,, and Y. Pommier. 1998. Molecular modeling studies of the DNAtopoisomerase I ternary cleavable complex with camptothecin. J. Med. Chem. 41: 2216– 2226.
87. Ferry, D. R.,, H. Traunecker,, and D. J. Kerr. 1996. Clinical trials of P-glycoprotein reversal in solid tumours. Eur. J. Cancer 32A: 1070– 1081.
88. Fisher, G. A.,, B. L. Lum,, J. Hausdorff,, and B. I. Sikic. 1996. Pharmacological considerations in the modulation of multidrug resistance. Eur. J. Cancer 32A: 1082– 1088.
89. Fisher, G. A.,, and B. I. Sikic. 1995. Clinical studies with modulators of multidrug resistance. Hematol. Oncol. Clin. North Am. 9: 363– 382.
90. Fojo, A. T.,, K. Ueda,, D. J. Slamon,, D. G. Poplack,, M. M. Gottesman,, and I. Pastan. 1987. Expression of a multidrugresistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA 84: 265– 269.
91. Fojo, T.,, and S. Bates. 2003. Strategies for reversing drug resistance. Oncogene 22: 7512– 7523.
92. Ford, J. M.,, and W. N. Hait. 1990. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol. Rev. 42: 155– 199.
93. Franklin, T. J.,, V. Jacobs,, P. Bruneau,, and P. Ple. 1995. Glucuronidation by human colorectal adenocarcinoma cells as a mechanism of resistance to mycophenolic acid. Adv. Enzyme Regul. 35: 91– 100.
94. Freemantle, S. J.,, A. L. Jackman,, L. R. Kelland,, A. H. Calvert,, and J. Lunec. 1995. Molecular characterisation of two cell lines selected for resistance to the folate-based thymidylate synthase inhibitor, ZD1694. Br. J. Cancer 71: 925– 930.
95. Freire, R.,, F. d’Adda Di Fagagna,, L. Wu,, G. Pedrazzi,, I. Stagljar,, I. D. Hickson,, and S. P. Jackson. 2001. Cleavage of the Bloom’s syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha. Nucleic Acids Res. 29: 3172– 3180.
96. Fry, D. W.,, J. C. Yalowich,, and I. D. Goldman. 1982. Rapid formation of poly-gamma-glutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by high pressure liquid chromatography in the Ehrlich ascites tumor cell in vitro. J. Biol. Chem. 257: 1890– 1896.
97. Fujimori, A.,, Y. Hoki,, N. C. Popescu,, and Y. Pommier. 1996. Silencing and selective methylation of the normal topoisomerase I gene in camptothecin-resistant CEM/C2 human leukemia cells. Oncol. Res. 8: 295– 301.
98. Galipeau, J.,, E. Benaim,, H. T. Spencer,, R. L. Blakley,, and B. P. Sorrentino. 1997. A bicistronic retroviral vector for protecting hematopoietic cells against antifolates and Pglycoprotein effluxed drugs. Hum. Gene Ther. 8: 1773– 1783.
99. Galmarini, C. M.,, E. Cros,, K. Graham,, X. Thomas,, J. R. Mackey,, and C. Dumontet. 2004. 5 -(3)-nucleotidase mRNA levels in blast cells are a prognostic factor in acute myeloid leukemia patients treated with cytarabine. Haematologica 89: 617– 619.
100. Galmarini, C. M.,, J. R. Mackey,, and C. Dumontet. 2001. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15: 875– 890.
101. Galmarini, C. M.,, X. Thomas,, F. Calvo,, P. Rousselot,, A. E. Jafaari,, E. Cros,, and C. Dumontet. 2002. Potential mechanisms of resistance to cytarabine in AML patients. Leuk. Res. 26: 621– 629.
102. Galmarini, C. M.,, X. Thomas,, F. Calvo,, P. Rousselot,, M. Rabilloud,, A. El Jaffari,, E. Cros,, and C. Dumontet. 2002. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br. J. Haematol. 117: 860– 868.
103. Gambacorti-Passerini, C. B.,, R. H. Gunby,, R. Piazza,, A. Galietta,, R. Rostagno,, and L. Scapozza. 2003. Molecular mechanisms of resistance to imatinib in Philadelphiachromosome-positive leukaemias. Lancet Oncol. 4: 75– 85.
104. Ganapathi, R.,, A. Constantinou,, N. Kamath,, G. Dubyak,, D. Grabowski,, and K. Krivacic. 1996. Resistance to etoposide in human leukemia HL-60 cells: reduction in druginduced DNA cleavage associated with hypophosphorylation of topoisomerase II phosphopeptides. Mol. Pharmacol. 50: 243– 248.
105. Gandhi, V.,, and W. Plunkett. 2002. Cellular and clinical pharmacology of fludarabine. Clin. Pharmacokinet. 41: 93– 103.
106. Gate, L.,, and K. D. Tew. 2001. Glutathione S-transferases as emerging therapeutic targets. Expert Opin. Ther. Targets 5: 477– 489.
107. Gati, W. P.,, A. R. Paterson,, A. R. Belch,, V. Chlumecky,, L. M. Larratt,, M. J. Mant,, and A. R. Turner. 1998. Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC). Leuk. Lymphoma 32: 45– 54.
108. Gellert, M. 1981. DNA topoisomerases. Annu. Rev. Biochem. 50: 879– 910.
109. Gerloff, T.,, B. Stieger,, B. Hagenbuch,, J. Madon,, L. Landmann,, J. Roth,, A. F. Hofmann,, and P. J. Meier. 1998. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273: 10046– 10050.
110. Germann, U. A. 1996. P-glycoprotein—a mediator of multidrug resistance in tumour cells. Eur. J. Cancer 32A: 927– 944.
111. Germann, U. A.,, T. C. Chambers,, S. V. Ambudkar,, T. Licht,, C. O. Cardarelli,, I. Pastan,, and M. M. Gottesman. 1996. Characterization of phosphorylation-defective mutants of human P-glycoprotein expressed in mammalian cells. J. Biol. Chem. 271: 1708– 1716.
112. Gibson, P.,, J. H. Gill,, P. A. Khan,, J. M. Seargent,, S. W. Martin,, P. A. Batman,, J. Griffith,, C. Bradley,, J. A. Double,, M. C. Bibby,, and P. M. Loadman. 2003. Cytochrome P450 1B1 (CYP1B1) is overexpressed in human colon adenocarcinomas relative to normal colon: implications for drug development. Mol. Cancer Ther. 2: 527– 534.
113. Glimelius, B.,, R. Ristamaki,, M. Kjaer,, P. Pfeiffer,, T. Skovsgaard,, K. M. Tveit,, T. Linne,, J. E. Frodin,, B. Boussard,, D. Oulid-Aissa,, and S. Pyrhonen. 2002. Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer. Ann. Oncol. 13: 1868– 1873.
114. Goan, Y. G.,, B. Zhou,, E. Hu,, S. Mi,, and Y. Yen. 1999. Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res. 59: 4204– 4207.
115. Goeptar, A. R.,, E. J. Groot,, H. Scheerens,, J. N. Commandeur,, and N. P. Vermeulen. 1994. Cytotoxicity of mitomycin C and adriamycin in freshly isolated rat hepatocytes: the role of cytochrome P450. Cancer Res. 54: 2411– 2418.
116. Goker, E.,, M. Waltham,, A. Kheradpour,, T. Trippett,, M. Mazumdar,, Y. Elisseyeff,, B. Schnieders,, P. Steinherz,, C. Tan,, and E. Berman. 1995. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 86: 677– 684.
117. Goldman, J. M.,, and J. V. Melo. 2001. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344: 1084– 1086.
118. Goldstein, L. J.,, H. Galski,, A. Fojo,, M. Willingham,, S. L. Lai,, A. Gazdar,, R. Pirker,, A. Green,, W. Crist,, G. M. Brodeur,, M. Lieber,, J. Cossman,, M. M. Gottesman,, and I. Pastan. 1989. Expression of a multidrug resistance gene in human cancers. J. Natl. Cancer Inst. 81: 116– 124.
119. Gorre, M. E.,, M. Mohammed,, K. Ellwood,, N. Hsu,, R. Paquette,, P. N. Rao,, and C. L. Sawyers. 2001. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876– 880.
120. Gottesman, M. M.,, T. Fojo,, and S. E. Bates. 2002. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2: 48– 58.
121. Gray, J. H.,, R. P. Owen,, and K. M. Giacomini. 2004. The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 447: 728– 734.
122. Guo, W.,, J. H. Healey,, P. A. Meyers,, M. Ladanyi,, A. G. Huvos,, J. R. Bertino,, and R. Gorlick. 1999. Mechanisms of methotrexate resistance in osteosarcoma. Clin. Cancer Res. 5: 621– 627.
123. Hainsworth, J.,, I. Vergote,, and J. Janssens. 2003. A review of phase II studies of ZD9331 treatment for relapsed or refractory solid tumours. Anticancer Drugs 14(Suppl 1): S13– S19.
124. Hamilton, T. C.,, M. A. Winker,, K. G. Louie,, G. Batist,, B. C. Behrens,, T. Tsuruo,, K. R. Grotzinger,, W. M. McKoy,, R. C. Young,, and R. F. Ozols. 1985. Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem. Pharmacol. 34: 2583– 2586.
125. Hande, K. R. 1998. Clinical applications of anticancer drugs targeted to topoisomerase II. Biochim. Biophys. Acta 1400: 173– 184.
126. Heidelberger, C.,, N. K. Chaudhuri,, P. Danneberg,, D. Mooren,, L. Griesbach,, R. Duschinsky,, R. J. Schnitzer,, E. Pleven,, and J. Scheiner. 1957. Fluorinated pyrimidines, a new class of tumour- inhibitory compounds. Nature 179: 663– 666.
127. Heisterkamp, N.,, G. Jenster,, J. ten Hoeve,, D. Zovich,, P. K. Pattengale,, and J. Groffen. 1990. Acute leukaemia in bcr/abl transgenic mice. Nature 344: 251– 253.
128. Hill, B. T.,, B. D. Bailey,, J. C. White,, and I. D. Goldman. 1979. Characteristics of transport of 4-amino antifolates and folate compounds by two lines of L5178Y lymphoblasts, one with impaired transport of methotrexate. Cancer Res. 39: 2440– 2446.
129. Hinds, M.,, K. Deisseroth,, J. Mayes,, E. Altschuler,, R. Jansen,, F. D. Ledley,, and L. A. Zwelling. 1991. Identification of a point mutation in the topoisomerase II gene from a human leukemia cell line containing an amsacrine-resistant form of topoisomerase II. Cancer Res. 51: 4729– 4731.
130. Hipfner, D. R.,, R. G. Deeley,, and S. P. Cole. 1999. Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 1461: 359– 376.
131. Hochhaus, A.,, S. Kreil,, A. S. Corbin,, P. La Rosee,, M. C. Muller,, T. Lahaye,, B. Hanfstein,, C. Schoch,, N. C. Cross,, U. Berger,, H. Gschaidmeier,, B. J. Druker,, and R. Hehlmann. 2002. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16: 2190– 2196.
132. Hochhauser, D.,, and A. L. Harris. 1993. The role of topoisomerase II alpha and beta in drug resistance. Cancer Treat. Rev. 19: 181– 194.
133. Holland, I. B. 2003. ABC Proteins: from Bacteria to Man. Academic Press, London.
134. Honjo, Y.,, C. A. Hrycyna,, Q. W. Yan,, W. Y. Medina-Perez,, R. W. Robey,, A. van de Laar,, T. Litman,, M. Dean,, and S. E. Bates. 2001. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCPoverexpressing cells. Cancer Res. 61: 6635– 6639.
135. Hooijberg, J. H.,, H. J. Broxterman,, M. Kool,, Y. G. Assaraf,, G. J. Peters,, P. Noordhuis,, R. J. Scheper,, P. Borst,, H. M. Pinedo,, and G. Jansen. 1999. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 59: 2532– 2535.
136. Horns, R. C., Jr.,, W. J. Dower,, and R. T. Schimke. 1984. Gene amplification in a leukemic patient treated with methotrexate. J. Clin. Oncol. 2: 2– 7.
137. Hrycyna, C. A. 2001. Molecular genetic analysis and biochemical characterization of mammalian P-glycoproteins involved in multidrug resistance. Semin. Cell Dev. Biol. 12: 247– 256.
138. Hsiung, Y.,, M. Jannatipour,, A. Rose,, J. McMahon,, D. Duncan,, and J. L. Nitiss. 1996. Functional expression of human topoisomerase II alpha in yeast: mutations at amino acids 450 or 803 of topoisomerase II alpha result in enzymes that can confer resistance to anti-topoisomerase II agents. Cancer Res. 56: 91– 99.
139. Huennekens, F. M.,, T. H. Duffy,, and K. S. Vitols. 1987. Folic acid metabolism and its disruption by pharmacologic agents. NCI Monogr. 5: 1– 8.
140. Husain, I.,, J. L. Mohler,, H. F. Seigler,, and J. M. Besterman. 1994. Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res. 54: 539– 546.
141. Ifergan, I.,, I. Meller,, J. Issakov,, and Y. G. Assaraf. 2003. Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity. Cancer 98: 1958– 1966.
142. Ito, K.,, S. L. Olsen,, W. Qiu,, R. G. Deeley,, and S. P. Cole. 2001. Mutation of a single conserved tryptophan in multidrug resistance protein 1 (MRP1/ABCC1) results in loss of drug resistance and selective loss of organic anion transport. J. Biol. Chem. 276: 15616– 15624.
143. Jackman, A. L.,, and A. H. Calvert. 1995. Folate-based thymidylate synthase inhibitors as anticancer drugs. Ann. Oncol. 6: 871– 881.
144. Jackman, A. L.,, L. R. Kelland,, R. Kimbell,, M. Brown,, W. Gibson,, G. W. Aherne,, A. Hardcastle,, and F. T. Boyle. 1995. Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines. Br. J. Cancer 71: 914– 924.
145. Jahns-Streubel, G.,, C. Reuter,, U. Auf der Landwehr,, M. Unterhalt,, E. Schleyer,, B. Wormann,, T. Buchner,, and W. Hiddemann. 1997. Activity of thymidine kinase and of polymerase alpha as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of granulocyte-macrophage colonystimulating factor-based priming before and during TAD-9 induction therapy in acute myeloid leukemia. Blood 90: 1968– 1976.
146. Jedlitschky, G.,, B. Burchell,, and D. Keppler. 2000. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J. Biol. Chem. 275: 30069– 30074.
147. Jedlitschky, G.,, I. Leier,, U. Buchholz,, K. Barnouin,, G. Kurz,, and D. Keppler. 1996. Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Res. 56: 988– 994.
148. Johnson, S. A. 2000. Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. Clin. Pharmacokinet. 39: 5– 26.
149. Johnston, P. G.,, H. J. Lenz,, C. G. Leichman,, K. D. Danenberg,, C. J. Allegra,, P. V. Danenberg,, and L. Leichman. 1995. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55: 1407– 1412.
150. Jolivet, J.,, and B. A. Chabner. 1983. Intracellular pharmacokinetics of methotrexate polyglutamates in human breast cancer cells. Selective retention and less dissociable binding of 4-NH2-10-CH3-pteroylglutamate4 and 4-NH2-10-CH3- pteroylglutamate5 to dihydrofolate reductase. J. Clin. Invest. 72: 773– 778.
151. Jolivet, J.,, R. L. Schilsky,, B. D. Bailey,, J. C. Drake,, and B. A. Chabner. 1982. Synthesis, retention, and biological activity of methotrexate polyglutamates in cultured human breast cancer cells. J. Clin. Invest. 70: 351– 360.
152. Jordan, M. A.,, and L. Wilson. 2004. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 4: 253– 265.
153. Juliano, R. L.,, and V. Ling. 1976. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455: 152– 162.
154. Kantarjian, H.,, C. Sawyers,, A. Hochhaus,, F. Guilhot,, C. Schiffer,, C. Gambacorti-Passerini,, D. Niederwieser,, D. Resta,, R. Capdeville,, U. Zoellner,, M. Talpaz,, B. Druker,, J. Goldman,, S. G. O’Brien,, N. Russell,, T. Fischer,, O. Ottmann,, P. Cony-Makhoul,, T. Facon,, R. Stone,, C. Miller,, M. Tallman,, R. Brown,, M. Schuster,, T. Loughran,, A. Gratwohl,, F. Mandelli,, G. Saglio,, M. Lazzarino,, D. Russo,, M. Baccarani,, and E. Morra. 2002. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346: 645– 652.
155. Kasid, U. N.,, B. Halligan,, L. F. Liu,, A. Dritschilo,, and M. Smulson. 1989. Poly(ADP-ribose)-mediated post-translational modification of chromatin-associated human topoisomerase I. Inhibitory effects on catalytic activity. J. Biol. Chem. 264: 18687– 18692.
156. Kaufman, R. J.,, P. C. Brown,, and R. T. Schimke. 1979. Amplified dihydrofolate reductase genes in unstably methotrexate- resistant cells are associated with double minute chromosomes. Proc. Natl. Acad. Sci. USA 76: 5669– 5673.
157. Kaufman, Y.,, S. Drori,, P. D. Cole,, B. A. Kamen,, J. Sirota,, I. Ifergan,, M. W. Arush,, R. Elhasid,, D. Sahar,, G. J. Kaspers,, G. Jansen,, L. H. Matherly,, G. Rechavi,, A. Toren,, and Y. G. Assaraf. 2004. Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia. Cancer 100: 773– 782.
158. Kaufmann, S. H.,, J. E. Karp,, R. J. Jones,, C. B. Miller,, E. Schneider,, L. A. Zwelling,, K. Cowan,, K. Wendel,, and P. J. Burke. 1994. Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. Blood 83: 517– 530.
159. Kaufmann, S. H.,, and D. L. Vaux. 2003. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22: 7414– 7430.
160. Kawasaki, H.,, C. J. Carrera,, L. D. Piro,, A. Saven,, T. J. Kipps,, and D. A. Carson. 1993. Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine. Blood 81: 597– 601.
161. Kawashiro, T.,, K. Yamashita,, X. J. Zhao,, E. Koyama,, M. Tani,, K. Chiba,, and T. Ishizaki. 1998. A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J. Pharmacol. Exp. Ther. 286: 1294– 1300.
162. Kellner, U.,, M. Sehested,, P. B. Jensen,, F. Gieseler,, and P. Rudolph. 2002. Culprit and victim —DNA topoisomerase II. Lancet Oncol. 3: 235– 243.
163. Kerr, D. J.,, J. Graham,, J. Cummings,, J. G. Morrison,, G. G. Thompson,, M. J. Brodie,, and S. B. Kaye. 1986. The effect of verapamil on the pharmacokinetics of adriamycin. Cancer Chemother. Pharmacol. 18: 239– 242.
164. Kerrigan, J. E.,, and D. S. Pilch. 2001. A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin. Biochemistry 40: 9792– 9798.
165. Khelifa, T.,, M. R. Casabianca-Pignede,, B. Rene,, and A. Jacquemin-Sablon. 1994. Expression of topoisomerases II alpha and beta in Chinese hamster lung cells resistant to topoisomerase II inhibitors. Mol. Pharmacol. 46: 323– 328.
166. Kitchens, M. E.,, A. M. Forsthoefel,, K. W. Barbour,, H. T. Spencer,, and F. G. Berger. 1999. Mechanisms of acquired resistance to thymidylate synthase inhibitors: the role of enzyme stability. Mol. Pharmacol. 56: 1063– 1070.
167. Kitchens, M. E.,, A. M. Forsthoefel,, Z. Rafique,, H. T. Spencer,, and F. G. Berger. 1999. Ligand-mediated induction of thymidylate synthase occurs by enzyme stabilization. Implications for autoregulation of translation. J. Biol. Chem. 274: 12544– 12547.
168. Kohler, T.,, C. Schill,, M. W. Deininger,, R. Krahl,, S. Borchert,, D. Hasenclever,, S. Leiblein,, O. Wagner,, and D. Niederwieser. 2002. High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML). Leukemia 16: 22– 29.
169. Kok, J. W.,, and H. Sietsma. 2004. Sphingolipid metabolism enzymes as targets for anticancer therapy. Curr. Drug Targets 5: 375– 382.
170. Komatani, H.,, H. Kotani,, Y. Hara,, R. Nakagawa,, M. Matsumoto,, H. Arakawa,, and S. Nishimura. 2001. Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure. Cancer Res. 61: 2827– 2832.
171. Kong, W.,, K. Engel,, and J. Wang. 2004. Mammalian nucleoside transporters. Curr. Drug Metab. 5: 63– 84.
172. Kool, M.,, M. van der Linden,, M. de Haas,, G. L. Scheffer,, J. M. de Vree,, A. J. Smith,, G. Jansen,, G. J. Peters,, N. Ponne,, R. J. Scheper,, R. P. Elferink,, F. Baas,, and P. Borst. 1999. MRP3, an organic anion transporter able to transport anticancer drugs. Proc. Natl. Acad. Sci. USA 96: 6914– 6919.
173. Kornberg, A.,, and T. A. Baker. 1992. DNA Replication, 2nd ed. W.H. Freeman, New York, N.Y.
174. Kruh, G. D. 2003. Introduction to resistance to anticancer agents. Oncogene 22: 7262– 7264.
175. Kubo, A.,, A. Yoshikawa,, T. Hirashima,, N. Masuda,, M. Takada,, J. Takahara,, M. Fukuoka,, and K. Nakagawa. 1996. Point mutations of the topoisomerase IIalpha gene in patients with small cell lung cancer treated with etoposide. Cancer Res. 56: 1232– 1236.
176. LaCasse, E. C.,, S. Baird,, R. G. Korneluk,, and A. E. MacKenzie. 1998. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17: 3247– 3259.
177. Laing, N. M.,, M. G. Belinsky,, G. D. Kruh,, D. W. Bell,, J. T. Boyd,, L. Barone,, J. R. Testa,, and K. D. Tew. 1998. Amplification of the ATP-binding cassette 2 transporter gene is functionally linked with enhanced efflux of estramustine in ovarian carcinoma cells. Cancer Res. 58: 1332– 1337.
178. Laliberte, J.,, and R. L. Momparler. 1994. Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA. Cancer Res. 54: 5401– 5407.
179. Larsen, A. K.,, and A. Skladanowski. 1998. Cellular resistance to topoisomerase-targeted drugs: from drug uptake to cell death. Biochim. Biophys. Acta 1400: 257– 274.
180. Le Saux, O.,, Z. Urban,, C. Tschuch,, K. Csiszar,, B. Bacchelli,, D. Quaglino,, I. Pasquali-Ronchetti,, F. M. Pope,, A. Richards,, S. Terry,, L. Bercovitch,, A. de Paepe,, and C. D. Boyd. 2000. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat. Genet. 25: 223– 227.
181. Lecureur, V.,, D. Sun,, P. Hargrove,, E. G. Schuetz,, R. B. Kim,, L. B. Lan,, and J. D. Schuetz. 2000. Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol. Pharmacol. 57: 24– 35.
182. Legrand, O.,, G. Simonin,, A. Beauchamp-Nicoud,, R. Zittoun,, and J. P. Marie. 1999. Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia. Blood 94: 1046– 1056.
183. Leichman, C. G.,, H. J. Lenz,, L. Leichman,, K. Danenberg,, J. Baranda,, S. Groshen,, W. Boswell,, R. Metzger,, M. Tan,, and P. V. Danenberg. 1997. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J. Clin. Oncol. 15: 3223– 3229.
184. Leith, C. P.,, K. J. Kopecky,, I. M. Chen,, L. Eijdems,, M. L. Slovak,, T. S. McConnell,, D. R. Head,, J. Weick,, M. R. Grever,, F. R. Appelbaum,, and C. L. Willman. 1999. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94: 1086– 1099.
185. Lenz, H. J.,, C. G. Leichman,, K. D. Danenberg,, P. V. Danenberg,, S. Groshen,, H. Cohen,, L. Laine,, P. Crookes,, H. Silberman,, J. Baranda,, Y. Garcia,, J. Li,, and L. Leichman. 1996. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J. Clin. Oncol. 14: 176– 182.
186. Leonard, G. D.,, T. Fojo,, and S. E. Bates. 2003. The role of ABC transporters in clinical practice. Oncologist 8: 411– 424.
187. Leslie, E. M.,, K. Ito,, P. Upadhyaya,, S. S. Hecht,, R. G. Deeley,, and S. P. Cole. 2001. Transport of the beta-O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1). Requirement for glutathione or a non-sulfur-containing analog. J. Biol. Chem. 276: 27846– 27854.
188. Leslie, E. M.,, Q. Mao,, C. J. Oleschuk,, R. G. Deeley,, and S. P. Cole. 2001. Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and atpase activities by interaction with dietary flavonoids. Mol. Pharmacol. 59: 1171– 1180.
189. Levy, A. S.,, H. N. Sather,, P. G. Steinherz,, R. Sowers,, M. La,, J. A. Moscow,, P. S. Gaynon,, F. M. Uckun,, J. R. Bertino,, and R. Gorlick. 2003. Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: a Children’s Cancer Group Study. J. Pediatr. Hematol. Oncol. 25: 688– 695.
190. Ling, V. 1992. Charles F. Kettering Prize. P-glycoprotein and resistance to anticancer drugs. Cancer 69: 2603– 2609.
191. Litman, T.,, T. E. Druley,, W. D. Stein,, and S. E. Bates. 2001. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell. Mol. Life Sci. 58: 931– 959.
192. Liu, L. F. 1989. DNA topoisomerase poisons as antitumor drugs. Annu. Rev. Biochem. 58: 351– 375.
193. Loe, D. W.,, R. G. Deeley,, and S. P. Cole. 1996. Biology of the multidrug resistance-associated protein, MRP. Eur. J. Cancer 32A: 945– 957.
194. Loe, D. W.,, R. G. Deeley,, and S. P. Cole. 1998. Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res. 58: 5130– 5136.
195. Loe, D. W.,, R. G. Deeley,, and S. P. Cole. 2000. Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). J. Pharmacol. Exp. Ther. 293: 530– 538.
196. Longley, D. B.,, P. R. Ferguson,, J. Boyer,, T. Latif,, M. Lynch,, P. Maxwell,, D. P. Harkin,, and P. G. Johnston. 2001. Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TStargeted chemotherapies. Clin. Cancer Res. 7: 3533– 3539.
197. Longo-Sorbello, G. S.,, and J. R. Bertino. 2001. Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials. Haematologica 86: 121– 127.
198. Loo, T. W.,, and D. M. Clarke. 2002. Location of the rhodamine-binding site in the human multidrug resistance Pglycoprotein. J. Biol. Chem. 277: 44332– 44338.
199. Loo, T. W.,, and D. M. Clarke. 1999. Merck Frosst Award Lecture 1998. Molecular dissection of the human multidrug resistance P-glycoprotein. Biochem. Cell Biol. 77: 11– 23.
200. Loo, T. W.,, and D. M. Clarke. 1999. The transmembrane domains of the human multidrug resistance P-glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface. J. Biol. Chem. 274: 24759– 24765.
201. Lotfi, K.,, G. Juliusson,, and F. Albertioni. 2003. Pharmacological basis for cladribine resistance. Leuk. Lymphoma 44: 1705– 1712.
202. Lu, X.,, S. Gong,, A. Monks,, D. Zaharevitz,, and J. A. Moscow. 2002. Correlation of nucleoside and nucleobase transporter gene expression with antimetabolite drug cytotoxicity. J. Exp. Ther. Oncol. 2: 200– 212.
203. Luduena, R. F. 1998. Multiple forms of tubulin: different gene products and covalent modifications. Int. Rev. Cytol. 178: 207– 275.
204. Lyttle, M. H.,, A. Satyam,, M. D. Hocker,, K. E. Bauer,, C. G. Caldwell,, H. C. Hui,, A. S. Morgan,, A. Mergia,, and L. M. Kauvar. 1994. Glutathione-S-transferase activates novel alkylating agents. J. Med. Chem. 37: 1501– 1507.
205. Mackey, J. R.,, L. L. Jennings,, M. L. Clarke,, C. L. Santos,, L. Dabbagh,, M. Vsianska,, S. L. Koski,, R. W. Coupland,, S. A. Baldwin,, J. D. Young,, and C. E. Cass. 2002. Immunohistochemical variation of human equilibrative nucleoside transporter 1 protein in primary breast cancers. Clin. Cancer Res. 8: 110– 116.
206. Mackey, J. R.,, R. S. Mani,, M. Selner,, D. Mowles,, J. D. Young,, J. A. Belt,, C. R. Crawford,, and C. E. Cass. 1998. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 58: 4349– 4357.
207. Mahdavian, E.,, H. T. Spencer,, and R. B. Dunlap. 1999. Kinetic studies on drug-resistant variants of Escherichia coli thymidylate synthase: functional effects of amino acid substitutions at residue 4. Arch. Biochem. Biophys. 368: 257– 264.
208. Mahon, F. X.,, M. W. Deininger,, B. Schultheis,, J. Chabrol,, J. Reiffers,, J. M. Goldman,, and J. V. Melo. 2000. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96: 1070– 1079.
209. Major, P. P.,, E. M. Egan,, G. P. Beardsley,, M. D. Minden,, and D. W. Kufe. 1981. Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA. Proc. Natl. Acad. Sci. USA 78: 3235– 3239.
210. Mapara, M. Y.,, and M. Sykes. 2004. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J. Clin. Oncol. 22: 1136– 1151.
211. Martello, L. A.,, H. M. McDaid,, D. L. Regl,, C. P. Yang,, D. Meng,, T. R. Pettus,, M. D. Kaufman,, H. Arimoto,, S. J. Danishefsky,, A. B. Smith, 3rd,, and S. B. Horwitz. 2000. Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines. Clin. Cancer Res. 6: 1978– 1987.
212. Matherly, L. H.,, D. W. Fry,, and I. D. Goldman. 1983. Role of methotrexate polyglutamylation and cellular energy metabolism in inhibition of methotrexate binding to dihydrofolate reductase by 5-formyltetrahydrofolate in Ehrlich ascites tumor cells in vitro. Cancer Res. 43: 2694– 2699.
213. Matsuda, A.,, and T. Sasaki. 2004. Antitumor activity of sugarmodified cytosine nucleosides. Cancer Sci. 95: 105– 111.
214. Mauritz, R.,, G. J. Peters,, D. G. Priest,, Y. G. Assaraf,, S. Drori,, I. Kathmann,, P. Noordhuis,, M. A. Bunni,, A. Rosowsky,, J. H. Schornagel,, H. M. Pinedo,, and G. Jansen. 2002. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem. Pharmacol. 63: 105– 115.
215. McFadyen, M. C.,, W. T. Melvin,, and G. I. Murray. 2004. Cytochrome P450 CYP1B1 activity in renal cell carcinoma. Br. J. Cancer 91: 966– 971.
216. McGuire, J. J. 2003. Anticancer antifolates: current status and future directions. Curr. Pharm. Des. 9: 2593– 2613.
217. McIvor, R. S.,, and C. C. Simonsen. 1990. Isolation and characterization of a variant dihydrofolate reductase cDNA from methotrexate-resistant murine L5178Y cells. Nucleic Acids Res. 18: 7025– 7032.
218. McLeod, H. L.,, and W. N. Keith. 1996. Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity. Br. J. Cancer 74: 508– 512.
219. Melera, P. W.,, J. P. Davide,, C. A. Hession,, and K. W. Scotto. 1984. Phenotypic expression in Escherichia coli and nucleotide sequence of two Chinese hamster lung cell cDNAs encoding different dihydrofolate reductases. Mol. Cell. Biol. 4: 38– 48.
220. Michieli, M.,, D. Damiani,, A. Ermacora,, P. Masolini,, D. Raspadori,, G. Visani,, R. J. Scheper,, and M. Baccarani. 1999. P-glycoprotein, lung resistance-related protein and multidrug resistance associated protein in de novo acute non-lymphocytic leukaemias: biological and clinical implications. Br. J. Haematol. 104: 328– 335.
221. Mini, E.,, S. Srimatkandada,, W. D. Medina,, B. A. Moroson,, M. D. Carman,, and J. R. Bertino. 1985. Molecular and karyological analysis of methotrexate-resistant and -sensitive human leukemic CCRF-CEM cells. Cancer Res. 45: 317– 324.
222. Miura, S.,, and S. Izuta. 2004. DNA polymerases as targets of anticancer nucleosides. Curr. Drug Targets 5: 191– 195.
223. Miyashita, T.,, and J. C. Reed. 1992. 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. 52: 5407– 5411.
224. Mo, Y. Y.,, Y. Yu,, Z. Shen,, and W. T. Beck. 2002. Nucleolar delocalization of human topoisomerase I in response to topotecan correlates with sumoylation of the protein. J. Biol. Chem. 277: 2958– 2964.
225. Modrak, D. E.,, M. D. Rodriguez,, D. M. Goldenberg,, W. Lew,, and R. D. Blumenthal. 2002. Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts. Int. J. Oncol. 20: 379– 384.
226. Momparler, R. L.,, and G. A. Fischer. 1968. Mammalian deoxynucleoside kinase. I. Deoxycytidine kinase: purification, properties, and kinetic studies with cytosine arabinoside. J. Biol. Chem. 243: 4298– 4304.
227. Moran, R. G.,, W. C. Werkheiser,, and S. F. Zakrzewski. 1976. Folate metabolism in mammalian cells in culture. I Partial characterization of the folate derivatives present in L1210 mouse leukemia cells. J. Biol. Chem. 251: 3569– 3575.
228. Morel, F.,, M. J. Bris,, A. Herry,, G. L. Calvez,, V. Marion,, J. F. Abgrall,, C. Berthou,, and M. D. Braekeleer. 2003. Double minutes containing amplified bcr-abl fusion gene in a case of chronic myeloid leukemia treated by imatinib. Eur. J. Haematol. 70: 235– 239.
229. Moscow, J. A. 1998. Methotrexate transport and resistance. Leuk. Lymphoma 30: 215– 224.

References: V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V.