Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Resistance to antifolates

Oncogene volume 22, pages 7431–7457 (2003)Cite this article

Abstract

The antifolates were the first class of antimetabolites to enter the clinics more than 50 years ago. Over the following decades, a full understanding of their mechanisms of action and chemotherapeutic potential evolved along with the mechanisms by which cells develop resistance to these drugs. These principals served as a basis for the subsequent exploration and understanding of the mechanisms of resistance to a variety of diverse antineoplastics with different cellular targets. This section describes the bases for intrinsic and acquired antifolate resistance within the context of the current understanding of the mechanisms of actions and cytotoxic determinants of these agents. This encompasses impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells. This chapter also describes how these insights are being utilized to develop gene therapy approaches to protect normal bone marrow progenitor cells as a strategy to improve the efficacy of bone marrow transplantation. Finally, clinical studies are reviewed that correlate the cellular pharmacology of methotrexate with the clinical outcome in children with neoplastic diseases treated with this antifolate.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

MTX:

methotrexate

DHFR:

dihydrofolate reductase

FPGS:

folylpolyglutamate synthetase

TS:

thymidylate synthase

γ-GH:

gamma glutamyl hydrolase

GARFT:

glycinamide ribonucleotide transformylase

AICARFT:

phosphoribosylaminoimidazolecarboxamide transformylase

5-CH3-THF:

5-methyl tetrahydrofolate

5-CHO-THF:

5-formyl tetrahydrofolate

5,10-CH2-THF:

5,10-methylene tetrahydrofolate

DHF:

dihydrofolate

THF:

tetrahydrofolate

dTMP:

deoxythymidylate

dUMP:

deoxyuridylate

SHMT:

serinehydroxymethyltransferase

TMD:

transmembrane domain

References

  • Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S and Matsuno S . (2001). Gastroenterology, 120, 1689–1699.

  • Aghi M, Kramm CM and Breakefield XO . (1999). J. Natl. Cancer Inst., 91, 1233–1241.

  • Alati T, Worzalla JF, Shih C, Bewley JR, Lewis S, Moran RG and Grindey GB . (1996). Cancer Res., 56, 2331–2335.

  • Albrecht AM, Biedler JL and Hutchison DJ . (1972). Cancer Res., 32, 1539–1546.

  • Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D and Jolivet J . (1985a). J. Biol. Chem., 260, 9720–9726.

  • Allegra CJ, Drake JC, Jolivet J and Chabner BA . (1985b). Proc. Natl. Acad. Sci. USA, 82, 4881–4885.

  • Allegra CJ, Fine R L, Drake JC and Chabner BA . (1986). J. Biol. Chem., 261, 6478–6485.

  • Allegra CJ, Hoang K, Yeh GC, Drake JC and Baram J . (1987). J. Biol. Chem., 262, 13520–13526.

  • Allen JD, Jackson SC and Schinkel AH . (2002). Cancer Res., 62, 2294–2299.

  • Andreassi JL and Moran RG . (2002). Biochemistry, 41, 226–235.

  • Appleman JR, Prendergast N, Delcamp TJ, Freisheim JH and Blakley RL . (1988). J. Biol. Chem., 263, 10304–10313.

  • Appling DR . (1991). FASEB J., 5, 2645–2651.

  • Arkin H, Ohnuma T, Kamen BA, Holland JF and Vallabhajosula S . (1989). Cancer Res., 49, 6556–6561.

  • Assaraf YG, Babani S and Goldman ID . (1998). J. Biol. Chem., 273, 8106–8111.

  • Assaraf YG and Goldman ID . (1997). J. Biol. Chem., 272, 17460–17466.

  • Assaraf YG, Molina A and Schimke RT . (1989). J. Natl. Cancer Inst., 81, 290–294.

  • Assaraf YG, Sierra EE, Babani S and Goldman ID . (1999). Biochem. Pharmacol., 58, 1321–1327.

  • Baggott JE, Vaughn WH and Hudson BB . (1986). Biochem. J., 236, 193–200.

  • Balinska M, Rhee M, Whiteley JM, Priest DG and Galivan J . (1991). Arch. Biochem. Biophys., 284, 219–222.

  • Banerjee D, Schweitzer BI, Volkenandt M, Li M-X, Waltham M, Mineishi S, Zhao S-C and Bertino JR . (1994). Gene, 139, 269–274.

  • Banerjee D, Tong Y, Liu-Chen X, Capiaux G, Ercikan-Abali EA, Takebe N, O'Connor OA and Bertino JR . (1999). Prog. Exp. Tumor Res., 36, 107–114.

  • Baram J, Allegra CJ, Fine RL and Chabner BA . (1987). J. Clin. Invest., 79, 692–697.

  • Barbour KW, Hoganson DK, Berger SH and Berger FG . (1992). Mol. Pharmacol., 42, 242–248.

  • Barnes MJ, Estlin EJ, Taylor GA, Aherne GW, Hardcastle A, McGuire JJ, Calvete JA, Lunec J, Pearson AD and Newell DR . (1999). Clin. Cancer Res., 5, 2548–2558.

  • Barredo JC, Synold TW, Laver J, Relling MV, Pui C-H, Priest DG and Evans WE . (1994). Blood, 84, 564–569.

  • Baugh CM, Krumdieck CL and Nair MG . (1973). Biochem. Biophys. Res. Commun., 52, 27–34.

  • Belkov VM, Krynetski EY, Schuetz JD, Yanishevski Y, Masson E, Mathew S, Raimondi S, Pui CH, Relling MV and Evans WE . (1999). Blood, 93, 1643–1650.

  • Bertino JR . (1977). Semin. Oncol., 4, 203–216.

  • Boritzki TJ, Barlett CA, Zhang C and Howland EF . (1996). Invest. New Drugs, 14, 295–303.

  • Borst P and Elferink RO . (2002). Annu. Rev. Biochem., 71, 537–592.

  • Borst P, Evers R, Kool M and Wijnholds J . (2000). J. Natl. Cancer Inst., 92, 1295–1302.

  • Brigle KE, Spinella MJ, Sierra EE and Goldman ID . (1995). J. Biol. Chem., 270, 22974–22979.

  • Brigle KE, Spinella MJ, Westin EH and Goldman ID . (1994). Biochem. Pharmacol., 47, 337–345.

  • Brigle KE, Westin EH, Houghton MT and Goldman ID . (1991). J. Biol. Chem., 266, 17243–17249.

  • Calvert H . (2002). Semin. Oncol., 29, 3–7.

  • Campbell IG, Jones TA, Foulkes WD and Trowsdale J . (1991). Cancer Res., 51, 5329–5338.

  • Capiaux GM, Budak-Alpdogan T, Takebe N, Mayer-Kuckuk P, Banerjee D, Maley F and Bertino JR . (2003). Hum. Gene. Ther., 14, 435–446.

  • Chabner BA, Allegra CJ, Curt GA, Clendeninn NJ, Baram J, Koizumi S, Drake JC and Jolivet J . (1985). J. Clin. Invest., 76, 907–912.

  • Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, Roon P, Ganapathy V and Smith SB . (2000). J. Biol. Chem., 275, 20676–20684.

  • Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS and Nicolas JP . (2000). Mol. Genet. Metab., 70, 310–315.

  • Chen ZS, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H and Kruh GD . (2002). Cancer Res., 62, 3144–3150.

  • Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE and Kruh GD . (2003). Cancer Res., 63, 4048–4054.

  • Chiao JH, Roy K, Tolner B, Yang CH and Sirotnak FM . (1997). J. Biol. Chem., 272, 11165–11170.

  • Chu E and Allegra CJ . (1996). Adv. Enzyme Regul., 36, 143–163.

  • Chu E, Drake JC, Boarman D, Baram J and Allegra CJ . (1990). J. Biol. Chem., 265, 8470–8478.

  • Chu E, Takimoto CH, Voeller D, Grem JL and Allegra CJ . (1993). Biochemistry, 32, 4756–4760.

  • Chu E, Voeller DM, Jones KL, Takechi T, Maley GF, Maley F, Segal S and Allegra CJ . (1994). Mol. Cell. Biol., 14, 207–213.

  • Chung K-N, Saikawa Y, Paik T-H, Dixon KH, Mulligan T, Cowan KH and Elwood PC . (1993). J. Clin. Invest., 91, 1289–1294.

  • Cole PD, Kamen BA, Gorlick R, Banerjee D, Smith AK, Magill E and Bertino JR . (2001). Cancer Res., 61, 4599–4604.

  • Coney LR, Tomassetti A, Carayannopoulos L, Frasca V, Kamen BA, Colnaghi MI and Zurawski Jr VR . (1991). Cancer Res., 51, 6125–6132.

  • Cowan KH and Jolivet J . (1984). J. Biol. Chem., 259, 10793–10800.

  • Curt GA, Carney DN, Cowan KH, Jolivet J, Bailey BD, Drake JC, Chien Song KS, Minna JD and Chabner BA . (1983). N. Engl. J. Med., 308, 199–202.

  • Curt GA, Jolivet J, Carney DN, Bailey BD, Drake JC, Clendeninn NJ and Chabner BA . (1985). J. Clin. Invest., 76, 1323–1329.

  • De Graaf D, Sharma RC, Mechetner EB, Schimke RT and Roninson IB . (1996). Proc. Natl. Acad. Sci. USA, 93, 1238–1242.

  • Dembo M, Sirotnak FM and Moccio DM . (1984). J. Membr. Biol., 78, 9–17.

  • Deutsch JC, Elwood PC, Portillo RM, Macey MG and Kolhouse JF . (1989). Arch. Biochem. Biophys., 274, 327–337.

  • Dicker AP, Volkenandt M, Schweitzer BI, Banerjee D and Bertino JR . (1990). J. Biol. Chem., 265, 8317–8321.

  • Dicker AP, Waltham MC, Volkenandt M, Schweitzer BI, Otter GM, Schmid FA, Sirotnak FM and Bertino JR . (1993). Proc. Natl. Acad. Sci. USA, 90, 11797–11801.

  • Ding BC, Witt TL, Hukku B, Heng H, Zhang L and Matherly LH . (2001). Biochem. Pharmacol., 61, 665–675.

  • Dixon KH, Lanpher BC, Chiu J, Kelley K and Cowan KH . (1994). J. Biol. Chem., 269, 17–20.

  • Dixon KH, Mulligan T, Chung K-N, Elwood PC and Cowan KH . (1992). J. Biol. Chem., 267, 24140–24147.

  • Dixon KH, Trepel JB, Eng SC and Cowan KH . (1991). Cancer Commun., 3, 357–365.

  • Dolnick BJ, Berenson RJ, Bertino JR, Kaufman RJ, Nunberg JH and Schimke RT . (1979). J. Cell Biol., 83, 394–402.

  • Domin BA, Cheng YC and Hakala MT . (1982). Mol. Pharmacol., 21, 231–238.

  • Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK and Ross DD . (1998). Proc. Natl. Acad. Sci. USA, 95, 15665–15670.

  • Drake JC, Allegra CJ, Moran RG and Johnston PG . (1996). Biochem. Pharmacol., 51, 1349–1355.

  • Drori S, Jansen G, Mauritz R, Peters GJ and Assaraf YG . (2000). J. Biol. Chem., 275, 30855–30863.

  • Dudeja PK, Torania SA and Said HM . (1997). Am. J. Physiol. Gastrointest. Liver Physiol., 272, G1408–G1415.

  • Ercikan-Abali EA, Banerjee D, Waltham MC, Skacel N, Scotto KW and Bertino JR . (1997). Biochemistry, 36, 12317–12322.

  • Ercikan E, Banerjee D, Waltham M, Schnieders B, Scotto KW and Bertino JR . (1993). Adv. Exp. Med. Biol., 338, 537–540.

  • Fabre I, Fabre G and Goldman ID . (1984). Cancer Res., 44, 3190–3195.

  • Farber S, Diamond LK, Mercer RD, Sylvester RF and Wolff VA . (1948). N. Engl. J. Med., 238, 787–793.

  • Ferguson PL and Flintoff WF . (1999). J. Biol. Chem., 274, 16269–16278.

  • Flasshove M, Banerjee D, Bertino JR and Moore MA . (1995a). Leukemia, 9 (Suppl. 1), S34–S37.

  • Flasshove M, Banerjee D, Mineishi S, Li MX, Bertino JR and Moore MA . (1995b). Blood, 85, 566–574.

  • Flintoff WF, Davidson SV and Siminovitch L . (1976). Somatic Cell Genet., 2, 245–261.

  • Freemantle SJ, Jackman AL, Kelland LR, Calvert AH and Lunec J . (1995). Br. J. Cancer, 71, 925–930.

  • Fry DW, Anderson LA, Borst M and Goldman ID . (1983). Cancer Res., 43, 1087–1092.

  • Fry DW, White JC and Goldman ID . (1980). Cancer Res., 40, 3669–3673.

  • Fry DW, Yalowich JC and Goldman ID . (1982a). Cancer Res., 42, 2532–2536.

  • Fry DW, Yalowich JC and Goldman ID . (1982b). J. Biol. Chem., 257, 1890–1896.

  • Fyfe MJ and Goldman ID . (1973). J. Biol. Chem., 248, 5067–5073.

  • Galipeau J, Benaim E, Spencer HT, Blakley RL and Sorrentino BP . (1997). Hum. Gene Ther., 8, 1773–1783.

  • Galivan J, Ryan TJ, Chave K, Rhee M, Yao R and Yin D . (2000). Pharmacol. Ther., 85, 207–215.

  • Galpin AJ, Schuetz JD, Masson E, Yanishevski Y, Synold TW, Barredo JC, Pui CH, Relling MV and Evans WE . (1997). Mol. Pharmacol., 52, 155–163.

  • Gifford AJ, Kavallaris M, Madafiglio J, Matherly LH, Stewart BW, Haber M and Norris M D . (1998). Int. J. Cancer, 78, 176–181.

  • Gifford AJ, Haber M, Witt TL, Whetstine JR, Taub JW, Matherly LH and Norris MD . (2002). Leukemia, 16, 2379–2387.

  • Goldie JH, Krystal G, Hartley D, Gudauskas G and Dedhar S . (1980). Eur. J. Cancer, 16, 1539–1546.

  • Goldman ID . (1969). J. Biol. Chem., 244, 3779–3785.

  • Goldman ID . (1971). Ann. NY Acad. Sci., 186, 400–422.

  • Goldman ID . (1974). Mol. Pharmacol., 10, 257–274.

  • Goldman ID, Lichtenstein NS and Oliverio VT . (1968). J. Biol. Chem., 243, 5007–5017.

  • Gorlick R, Goker E, Trippett T, Steinherz P, Elisseyeff Y, Mazumdar M, Flintoff WF and Bertino JR . (1997). Blood, 89, 1013–1018.

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN and Sawyers CL . (2001). Science, 293, 876–880.

  • Göker E, Lin JT, Trippett T, Elisseyeff Y, Tong WP, Niedzwiecki D, Tan C, Steinherz P, Schweitzer BI and Bertino JR . (1993). Leukemia, 7, 1000–1004.

  • Gottesman MM and Pastan I . (1993). Annu. Rev. Biochem., 62, 385–427.

  • Guo W, Healey JH, Meyers PA, Ladanyi M, Huvos AG, Bertino JR and Gorlick R . (1999). Clin. Cancer Res., 5, 621–627.

  • Habeck LL, Mendelsohn LG, Shih C, Taylor EC, Colman PD, Gossett LS, Leitner TA, Schultz RM, Andis SL and Moran RG . (1995). Mol. Pharmacol., 48, 326–333.

  • Hakala MT . (1965). Biochim. Biophys. Acta, 102, 210–225.

  • Heidelberger C, Chaudhuari NK and Danncnberg P et al. (1957). Nature, 179, 663.

  • Henderson GB and Strauss BP . (1990a). Cancer Res., 50, 1709–1714.

  • Henderson GB and Strauss BP . (1990b). Biochem. Pharmacol., 39, 2019–2025.

  • Henderson GB, Tsuji JM and Kumar HP . (1988). J. Membr. Biol., 101, 247–258.

  • Henderson GB and Zevely EM . (1981). Biochem. Biophys. Res. Commun., 99, 163–169.

  • Henderson GB and Zevely EM . (1982a). Biochem. Int., 4, 493–502.

  • Henderson GB and Zevely EM . (1982b). Biochem. Biophys. Res. Commun., 104, 474–482.

  • Henderson GB and Zevely EM . (1983). Arch. Biochem. Biophys., 221, 438–446.

  • Henderson GB and Zevely EM . (1984a). J. Biol. Chem., 259, 4558–4562.

  • Henderson GB and Zevely EM . (1984b). J. Biol. Chem., 259, 1526–1531.

  • Higgins CF and Gottesman MM . (1992). Trends Biochem. Sci., 17, 18–21.

  • Hill BT, Bailey BD, White JC and Goldman ID . (1979). Cancer Res., 39, 2440–2446.

  • Hirohashi T, Suzuki H and Sugiyama Y . (1999). J. Biol. Chem., 274, 15181–15185.

  • Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de LA, Litman T, Dean M and Bates SE . (2001). Cancer Res., 61, 6635–6639.

  • Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P, Scheper RJ, Borst P, Pinedo HM and Jansen G . (1999). Cancer Res., 59, 2532–2535.

  • Hooijberg JH, Peters GJ, Assaraf YG, Kathmann I, Priest DG, Bunni MA, Veerman AJ, Scheffer GL, Kaspers GJ and Jansen G . (2003). Biochem. Pharmacol., 65, 765–771.

  • Horne DW . (1990). Biochim. Biophys. Acta Bio-Membr., 1023, 47–55.

  • Horne DW and Reed KA . (2001). Arch. Biochem. Biophys., 394, 39–44.

  • Horns Jr RC, Dower WJ and Schimke RT . (1984). J. Clin. Oncol., 2, 2–7.

  • Houghton PJ, Rahman A, Will CL, Dolnick BJ and Houghton JA . (1992). Cancer Res., 52, 558–565.

  • Hsueh C-T and Dolnick BJ . (1994). Biochem. Pharmacol., 47, 1019–1027.

  • Huang W, Prasad PD, Kekuda R, Leibach FH and Ganapathy V . (1997). Invest. Ophthalmol. Vis. Sci., 38, 1578–1587.

  • Ito K, Oleschuk CJ, Westlake C, Vasa MZ, Deeley RG and Cole SP . (2001). J. Biol. Chem., 276, 38108–38114.

  • Jackman AL, Kelland LR, Kimbell R, Brown M, Gibson W, Aherne GW, Hardcastle A and Boyle FT . (1995). Br. J. Cancer, 71, 914–924.

  • Jackman AL, Kimbell R, Aherne GW, Brunton L, Jansen G, Stephens TC, Smith MN, Wardleworth JM and Boyle FT . (1997). Clin. Cancer Res., 3, 911–921.

  • Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR and Hughes LR . (1991). Cancer Res., 51, 5579–5586.

  • Jackson RC, Fry DW, Boritzki TJ, Besserer JA, Leopold WR, Sloan BJ and Elslager EF . (1984). Adv. Enzyme Regul., 22, 187–206.

  • Jackson RC and Harrap KR . (1973). Arch. Biochem. Biophys., 158, 827–841.

  • Jackson RC, Hart LI and Harrap KR . (1976). Cancer Res., 36, 1991–1997.

  • Jackson RC, Niethammer D and Hart LI . (1977). Arch. Biochem. Biophys., 182, 646–656.

  • Jansen G, Barr H, Kathmann I, Bunni MA, Priest DG, Noordhuis P, Peters GJ and Assaraf YG . (1999). Mol. Pharmacol., 55, 761–769.

  • Jansen G, Kathmann I, Rademaker BC, Braakhuis BJM, Westerhof GR, Rijksen G and Schornagel JH . (1989). Cancer Res., 49, 1959–1963.

  • Jansen G, Mauritz R, Drori S, Sprecher H, Kathmann I, Bunni M, Priest DG, Noordhuis P, Schornagel JH, Pinedo HM, Peters GJ and Assaraf YG . (1998). J. Biol. Chem., 273, 30189–30198.

  • Jansen G, Schornagel JH, Westerhof GR, Rijksen G, Newell DR and Jackman AL . (1990). Cancer Res., 50, 7544–7548.

  • Johnson TB, Nair MG and Galivan J . (1988). Cancer Res., 48, 2426–2431.

  • Jolivet J and Chabner BA . (1983). J. Clin. Invest., 72, 773–778.

  • Jolivet J, Schilsky RL, Bailey BD, Drake JC and Chabner BA . (1982). J. Clin. Invest., 70, 351–360.

  • Juliano RL and Ling V . (1976). Biochim. Biophys. Acta, 455, 152–162.

  • Kamen BA, Wang M-T, Streckfuss AJ, Peryea X and Anderson RGW . (1988). J. Biol. Chem., 263, 13602–13609.

  • Kane MA, Portillo RM, Elwood PC, Antony AC and Kolhouse JF . (1986). J. Biol. Chem., 261, 44–49.

  • Kates RE, Tozer TN and Sorby DL . (1976). Biochem. Pharmacol., 25, 1485–1488.

  • Kaufman RJ, Brown PC and Schimke RT . (1979). Proc. Natl. Acad. Sci. USA, 76, 5669–5673.

  • Khokhar NZ, She Y, Rusch VW and Sirotnak FM . (2001). Clin. Cancer Res., 7, 3199–3205.

  • Kim J-S, Lowe KE and Shane B . (1993). J. Biol. Chem., 268, 21680–21685.

  • Kitchens ME, Forsthoefel AM, Barbour KW, Spencer HT and Berger FG . (1999a). Mol. Pharmacol., 56, 1063–1070.

  • Kitchens ME, Forsthoefel AM, Rafique Z, Spencer HT and Berger FG . (1999b). J. Biol. Chem., 274, 12544–12547.

  • Koizumi S, Curt GA, Fine RL, Griffin JD and Chabner BA . (1985). J. Clin. Invest., 75, 1008–1014.

  • Koizumi S, Ueno Y, Ohno I, Ichihara T, Tamaru Y and Matsukawa H . (1990). Jpn. J. Cancer Res., 81, 1162–1167.

  • Kool M, van der LM, de Haas M, Scheffer GL, de Vree JM, Smith AJ, Jansen G, Peters GJ, Ponne N, Scheper RJ, Elferink RP, Baas F and Borst P . (1999). Proc. Natl. Acad. Sci. USA, 96, 6914–6919.

  • Kuhnel JM, Chiao JH and Sirotnak FM . (2000). J. Cell. Physiol., 184, 364–372.

  • Kumar CK, Nguyen TT, Gonzales FB and Said HM . (1998). Am. J. Physiol., 274, C289–C294.

  • Kumar P, Kisliuk RL, Gaumont Y, Freisheim JH and Nair MG . (1989). Biochem. Pharmacol., 38, 541–543.

  • Kusuhara H, Han YH, Shimoda M, Kokue E, Suzuki H and Sugiyama Y . (1998). Am. J. Physiol., 275, G789–G796.

  • Leamon CP and Low PS . (2001). Drug Discov.Today, 6, 44–51.

  • Lee K, Klein-Szanto AJ and Kruh GD . (2000). J. Natl. Cancer Inst., 92, 1934–1940.

  • Li W-W, Lin JT, Schweitzer BI, Tong WP, Niedzwiecki D and Bertino JR . (1992a). Cancer Res., 52, 3908–3913.

  • Liani E, Rothem L, Bunni MA, Smith CA, Jansen G and Assaraf YG . (2003). Int. J. Cancer, 103, 587–599.

  • Li W-W, Lin JT, Tong WP, Trippett TM, Brennan MF and Bertino JR . (1992b). Cancer Res., 52, 1434–1438.

  • Litman T, Druley TE, Stein WD and Bates SE . (2001). Cell Mol. Life Sci., 58, 931–959.

  • Liu XY and Matherly LH . (2001). Biochem. J., 358, 511–516.

  • Liu X and Matherly L . (2002). Biochim. Biophys. Acta, 1564, 333–342.

  • Longley DB, Ferguson PR, Boyer J, Latif T, Lynch M, Maxwell P, Harkin DP and Johnston PG . (2001). Clin. Cancer Res., 7, 3533–3539.

  • Longo GS, Gorlick R, Tong WP, Lin S, Steinherz P and Bertino JR . (1997). Oncol. Res., 9, 259–263.

  • Lu K, Yin M-B, McGuire JJ, Bonmassar E and Rustum YM . (1995). Biochem. Pharmacol., 50, 391–398.

  • Lu Y and Low P . (2002). Adv. Drug Deliv. Rev., 54, 675.

  • Mahdavian E, Spencer HT and Dunlap RB . (1999). Arch. Biochem. Biophys., 368, 257–264.

  • Masson E, Relling MV, Synold TW, Liu Q, Schuetz JD, Sandlund JT, Pui CH and Evans WE . (1996). J. Clin. Invest., 97, 73–80.

  • Masuda M, I'izuka Y, Yamazaki M, Nishigaki R, Kato Y, Ni'inuma K, Suzuki H and Sugiyama Y . (1997). Cancer Res., 57, 3506–3510.

  • Masuda S, Ibaramoto K, Takeuchi A, Saito H, Hashimoto Y and Inui KI . (1999). Mol. Pharmacol., 55, 743–752.

  • Matherly LH . (2001). Prog. Nucleic Acid Res. Mol. Biol., 67, 131–162.

  • Matherly LH, Anderson LA and Goldman ID . (1984). Cancer Res., 44, 2325–2330.

  • Matherly LH, Angeles SM and McGuire JJ . (1993). Biochem. Pharmacol., 46, 2185–2195.

  • Matherly LH, Barlowe CK and Goldman ID . (1986). Cancer Res., 46, 588–593.

  • Matherly LH, Barlowe CK, Phillips VM and Goldman ID . (1987). J. Biol. Chem., 262, 710–717.

  • Matherly LH, Czajkowski CA, Muench SP and Psiakis JT . (1990). Cancer Res., 50, 3262–3269.

  • Matherly LH, Fry DW and Goldman ID . (1983). Cancer Res., 43, 2694–2699.

  • Matherly LH and Muench SP . (1990). Biochem. Pharmacol., 39, 2005–2014.

  • Matherly LH, Taub JW, Ravindranath Y, Proefke SA, Wong SC, Gimotty P, Buck S, Wright JE and Rosowsky A . (1995). Blood, 85, 500–509.

  • Matherly LH and Goldman DI . (2003). Vitam. Horm., 66, 403–456.

  • Mauritz R, Peters GJ, Priest DG, Assaraf YG, Drori S, Kathmann I, Noordhuis P, Bunni MA, Rosowsky A, Schornagel JH, Pinedo HM and Jansen G . (2002). Biochem. Pharmacol., 63, 105–115.

  • McBurney MW and Whitmore GF . (1974). Cell, 2, 173–182.

  • McCloskey DE, McGuire JJ, Russell CA, Rowan BG, Bertino JR, Pizzorno G and Mini E . (1991). J. Biol. Chem., 266, 6181–6187.

  • McGuire JJ, Haile WH, Russell CA, Galvin JM and Shane B . (1995). Oncol. Res., 7, 535–543.

  • McGuire JJ and Russell CA . (1998). Oncol. Res., 10, 193–200.

  • McIvor RS and Simonsen CC . (1990). Nucleic Acids Res., 18, 7025–7032.

  • Melera PW, Davide JP, Hession CA and Scotto KW . (1984). Mol. Cell. Biol., 4, 38–48.

  • Melera PW, Davide JP and Oen H . (1988). J. Biol. Chem., 263, 1978–1990.

  • Merickel A, Kaback HR and Edwards RH . (1997). J. Biol. Chem., 272, 5403–5408.

  • Mineo C and Anderson RG . (2001). Histochem. Cell Biol., 116, 109–118.

  • Mini E, Srimatkandada S, Medina WD, Moroson BA, Carman MD and Bertino JR . (1985). Cancer Res., 45, 317–324.

  • Miotti S, Facheris P, Tomassetti A, Bottero F, Bottini C, Ottone F, Colnaghi MI, Bunni MA, Priest DG and Canevari S . (1995). Int. J. Cancer, 63, 395–401.

  • Miyachi H, Takemura Y, Kobayashi H and Ando Y . (1995). Cancer Lett., 88, 93–99.

  • Moran RG, Werkheiser WC and Zakrzewski SF . (1976). J. Biol. Chem., 251, 3569–3575.

  • Moscow JA, Gong MK, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS and Cowan KH . (1995). Cancer Res., 55, 3790–3794.

  • Niethammer D and Jackson RC . (1975). Eur. J. Cancer, 11, 845–854.

  • Nimec Z and Galivan J . (1983). Arch. Biochem. Biophys., 226, 671–680.

  • Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ, Stabler SP, Paoletti P, Calvert AH and Allen RH . (2002). Mol. Cancer Ther., 1, 545–552.

  • Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV and Roninson IB . (1996). Int. J. Cancer, 65, 613–619.

  • O'Connor BM, Jackman AL, Crossley PH, Freemantle SJ, Lunec J and Calvert AH . (1992). Cancer Res., 52, 1137–1143.

  • Pan XQ, Zheng X, Shi G, Wang H, Ratnam M and Lee RJ . (2002). Blood, 100, 594–602.

  • Pisters KM, Tyson LB, Tong W, Fleisher M, Miller VA, Grant SC, Pfister DG, Rigas JR, Densmore CL, Krol G, Heelan RT, Sirotnak FM, Bertino JR and Kris MG . (1996). Clin. Cancer Res., 2, 1819–1824.

  • Pizzorno G, Chang YM, McGuire JJ and Bertino JR . (1989). Cancer Res., 49, 5275–5280.

  • Pizzorno G, Mini E, Coronnello M, McGuire JJ, Moroson BA, Cashmore AR, Dreyer RN, Lin JT, Mazzei T and Periti P . (1988). Cancer Res., 48, 2149–2155.

  • Pizzorno G, Moroson BA, Cashmore AR, Russello O, Mayer JR, Galivan J, Bunni MA, Priest DG and Beardsley GP . (1995). Cancer Res., 55, 566–573.

  • Pizzorno G, Sokoloski JA, Cashmore AR, Moroson BA, Cross AD and Beardsley GP . (1991). Mol. Pharmacol., 39, 85–89.

  • Poser RG, Sirotnak FM and Chello PL . (1981). Cancer Res., 41, 4441–4446.

  • Prasad PD, Ramamoorthy S, Leibach FH and Ganapathy V . (1995). Biochem. Biophys. Res. Commun., 206, 681–687.

  • Priest DG, Bunni M and Sirotnak FM . (1989). Cancer Res., 49, 4204–4209.

  • Ragoussis J, Senger G, Trowsdale J and Campbell IG . (1992). Genomics, 14, 423–430.

  • Rajgopal A, Sierra EE, Zhao R and Goldman ID . (2001). Am. J. Physiol. Cell. Physiol., 281, C1579–C1586.

  • Ratnam M, Marquardt H, Duhring JL and Freisheim JH . (1989). Biochemistry, 28, 8249–8254.

  • Reddy JA, Haneline LS, Srour EF, Antony AC, Clapp DW and Low PS . (1999). Blood, 93, 3940–3948.

  • Reilly RT, Forsthoefel AM and Berger FG . (1997). Arch. Biochem. Biophys., 342, 338–343.

  • Rhee MS, Balinska M, Bunni M, Priest DG, Maley GF, Maley F and Galivan J . (1990). Cancer Res., 50, 3979–3984.

  • Rhee MS, Wang Y, Nair MG and Galivan J . (1993). Cancer Res., 53, 2227–2230.

  • Roberts JD, Poplin EA, Tombes MB, Kyle B, Spicer DV, Grant S, Synold T and Moran R . (2000). Cancer Chemother. Pharmacol., 45, 103–110.

  • Rosenblatt DS, Whitehead VM, Dupont MM, Vuchich MJ and Vera N . (1978a). Mol. Pharmacol., 14, 210–214.

  • Rosenblatt DS, Whitehead VM, Vera N, Pottier A, Dupont M and Vuchich MJ . (1978b). Mol. Pharmacol., 14, 1143–1147.

  • Rosowsky A, Wright JE, Vaidya CM, Bader H, Forsch RA, Mota CE, Pardo J, Chen CS and Chen YN . (1998). J. Med. Chem., 41, 5310–5319.

  • Rosowsky A, Wright JE, Vaidya CM and Forsch RA . (2000). Pharmacol. Ther., 85, 191–205.

  • Ross JF, Chaudhuri PK and Ratnam M . (1994). Cancer, 73, 2432–2443.

  • Ross DD, Yang W, Abruzzo LV, Dalton WS, Schneider E, Lage H, Dietel M, Greenberger L, Cole SP and Doyle LA . (1999a). J. Natl. Cancer Inst., 91, 429–433.

  • Ross JF, Wang H, Behm FG, Mathew P, Wu M, Booth R and Ratnam M . (1999b). Cancer, 85, 348–357.

  • Rothem L, Ifergan I, Kaufman Y, Priest DG, Jansen G and Assaraf YG . (2002). Biochem. J., 367, 741–750.

  • Rothem L, Aronheim A and Assaraf YG . (2003). J. Biol. Chem., 278, 8935–8941.

  • Rots MG, Pieters R, Peters GJ, van Zantwijk CH, Mauritz R, Noordhuis P, Willey JC, Hahlen K, Creutzig U, Janka-Schaub G, Kaspers GJ, Veerman AJ and Jansen G . (1999). Blood, 94, 3121–3128.

  • Roy K, Egan MG, Sirlin S and Sirotnak FM . (1997). J. Biol. Chem., 272, 6903–6908.

  • Roy K, Tolner B, Chiao JH and Sirotnak FM . (1998). J. Biol. Chem., 273, 2526–2531.

  • Russel FG, Masereeuw R and van Aubel RA . (2002). Annu. Rev. Physiol., 64, 563–594.

  • Sadasivan E and Rothenberg SP . (1989). J. Biol. Chem., 264, 5806–5811.

  • Sahin-Toth M, Dunten RL, Gonzalez A and Kaback HR . (1992). Proc. Natl. Acad. Sci. USA, 89, 10547–10551.

  • Saikawa Y, Knight CB, Saikawa T, Page ST, Chabner BA and Elwood PC . (1993). J. Biol. Chem., 268, 5293–5301.

  • Saito H, Masuda S and Inui K . (1996). J. Biol. Chem., 271, 20719–20725.

  • Sanghani SP and Moran RG . (1997). Biochemistry, 36, 10506–10516.

  • Sanghani SP, Sanghani PC and Moran RG . (1999). J. Biol. Chem., 274, 27018–27027.

  • Sauerbrey A, McPherson JP, Zhao SC, Banerjee D and Bertino JR . (1999). Hum. Gene Ther., 10, 2495–2504.

  • Saxena M and Henderson GB . (1995). J. Biol. Chem., 270, 5312–5319.

  • Saxena M and Henderson GB . (1996). Biochem. Pharmacol., 51, 975–982.

  • Schilsky RL, Bailey BD and Chabner BA . (1980). Proc. Natl. Acad. Sci. USA, 77, 2919–2922.

  • Schimke RT . (1988). J. Biol. Chem., 263, 5989–5992.

  • Schirch V and Strong WB . (1989). Arch. Biochem. Biophys., 269, 371–380.

  • Schlemmer SR and Sirotnak FM . (1992). J. Biol. Chem., 267, 14746–14752.

  • Schlemmer SR and Sirotnak FM . (1995). Biochem. Pharmacol., 49, 1427–1433.

  • Schmitz JC, Liu J, Lin X, Chen TM, Yan W, Tai N, Gollerkeri A and Chu E . (2001). Cancer Metastasis Rev., 20, 33–41.

  • Schuetz JD, Matherly LH, Westin EH and Goldman ID . (1988). J. Biol. Chem., 263, 9840–9847.

  • Schultz RM, Chen VJ, Bewley JR, Roberts EF, Shih C and Dempsey JA . (1999). Semin. Oncol., 26, 68–73.

  • Seither RL, Trent DF, Mikullecky DC, Rape TJ and Goldman ID . (1989). J. Biol. Chem., 264, 17016–17023.

  • Seither RL, Trent DF, Mikullecky DC, Rape TJ and Goldman ID . (1991). J. Biol. Chem., 266, 4112–4118.

  • Selhub J, Dhar GJ and Rosenberg IH . (1983). Pharmacol. Ther., 20, 397–418.

  • Sharif KA, Moscow JA and Goldman ID . (1998). Biochem. Pharmacol., 55, 1683–1689.

  • Sharina IG, Zhao R, Wang Y, Babani S and Goldman ID . (2001). Mol. Pharmacol., 59, 1022–1028.

  • Shen F, Ross JF, Wang X and Ratnam M . (1994). Biochemistry, 33, 1209–1215.

  • Shen F, Wu M, Ross JF, Miller D and Ratnam M . (1995). Biochemistry, 34, 5660–5665.

  • Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M and Schultz RM . (1997). Cancer Res., 57, 1116–1123.

  • Sierra EE, Brigle KE, Spinella MJ and Goldman ID . (1997). Biochem. Pharmacol., 53, 223–231.

  • Sierra EE and Goldman ID . (1998). Biochem. Pharmacol., 55, 1505–1512.

  • Simonsen CC and Levinson AD . (1983). Proc. Natl. Acad. Sci. USA, 80, 2495–2499.

  • Sirotnak FM and Donsbach RC . (1974). Cancer Res., 34, 332–340.

  • Sirotnak FM, Goutas LJ, Jacobsen DM, Mines LS, Barrueco JR, Gaumont Y and Kisliuk RL . (1987). Biochem. Pharmacol., 36, 1659–1667.

  • Sirotnak FM, Kurita S and Hutchison DJ . (1968). Cancer Res., 28, 75–80.

  • Sirotnak FM, Moccio DM and Dorick DM . (1978). Cancer Res., 38, 345–353.

  • Sirotnak FM, Moccio DM, Hancock CH and Young CW . (1981a). Cancer Res., 41, 3944–3949.

  • Sirotnak FM, Moccio DM, Kelleher LE and Goutas LJ . (1981b). Cancer Res., 41, 4447–4452.

  • Sirotnak FM, Moccio DM and Young CW . (1981c). Cancer Res., 41, 966–970.

  • Sirotnak FM and Tolner B . (1999). Annu. Rev. Nutr., 19, 91–122.

  • Sirotnak FM, Wendel HG, Bornmann WG, Tong WP, Miller VA, Scher HI and Kris MG . (2000). Clin. Cancer Res., 6, 3705–3712.

  • Sorrentino BP, Allay JA and Blakley RL . (1999). Prog. Exp. Tumor Res., 36, 143–161.

  • Spencer HT, Sorrentino BP, Pui CH, Chunduru SK, Sleep SE and Blakley RL . (1996). Leukemia, 10, 439–446.

  • Spinella MJ, Brigle KE, Sierra EE and Goldman ID . (1995). J. Biol. Chem., 270, 7842–7849.

  • Srimatkandada S, Schweitzer BI, Moroson BA, Dube S and Bertino JR . (1989). J. Biol. Chem., 264, 3524–3528.

  • Stein WD . (1997). Physiol. Rev., 77, 545–590.

  • Stokstad ELR . (1990). Folic Acid Metabolism in Health and Disease. Picciano MF, Stokstad ELR (eds). Wiley-Liss: New York, pp 1–21.

    Google Scholar 

  • Sun W, Wu RR, van Poelje PD and Erion MD . (2001). Biochem. Biophys. Res. Commun., 283, 417–422.

  • Sun X, Bognar AL, Baker EN and Smith CA . (1998). Proc. Natl. Acad. Sci. USA, 95, 6647–6652.

  • Synold TW, Relling MV, Boyett JM, Rivera GK, Sandlund JT, Mahmoud H, Crist WM, Pui C-H and Evans WE . (1994). J. Clin. Invest., 94, 1996–2001.

  • Stark M, Rothem L, Jansen G, Scheffer GL, Goldman ID and Assaraf YG . (2003). Mol Pharmacol., 64, 220–227.

  • Takebe N, Nakahara S, Zhao SC, Adhikari D, Ural AU, Iwamoto M, Banerjee D and Bertino JR . (2000). Cancer Gene Ther., 7, 910–919.

  • Takebe N, Zhao SC, Adhikari D, Mineishi S, Sadelain M, Hilton J, Colvin M, Banerjee D and Bertino JR . (2001). Mol. Ther., 3, 88–96.

  • Theti DS, Bavetsias V, Skelton LA, Titley J, Gibbs D, Jansen G and Jackman AL . (2003). Cancer Res., 63, 3612–3618.

  • Tong Y, Liu-Chen X, Ercikan-Abali EA, Capiaux GM, Zhao SC, Banerjee D and Bertino JR . (1998a). J. Biol. Chem., 273, 11611–11618.

  • Tong Y, Liu-Chen X, Ercikan-Abali EA, Zhao SC, Banerjee D, Maley F and Bertino JR . (1998b). J. Biol. Chem., 273, 31209–31214.

  • Trent DF, Seither RL and Goldman ID . (1991a). Biochem. Pharmacol., 42, 1015–1019.

  • Trent DF, Seither RL and Goldman ID . (1991b). J. Biol. Chem., 266, 5445–5449.

  • Trent JM, Buick RN, Olson S, Horns Jr RC and Schimke RT . (1984). J. Clin. Oncol., 2, 8–15.

  • Tse A, Brigle K, Taylor SM and Moran RG . (1998). J. Biol. Chem., 273, 25953–25960.

  • Tse A and Moran RG . (1998). J. Biol. Chem., 273, 25944–25952.

  • Van der Veer LJ, Westerhof GR, Rijksen G, Schornagel JH and Jansen G . (1989). Leukemia Res., 13, 981–987.

  • Van der Wilt CL, Backus HH, Smid K, Comijn L, Veerman G, Wouters D, Voorn DA, Priest DG, Bunni MA, Mitchell F, Jackman AL, Jansen G and Peters GJ . (2001). Cancer Res., 61, 3675–3681.

  • Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C and Paoletti P . (2003). J. Clin. Oncol., 21, 2636–2644.

  • Volk EL, Farley KM, Wu Y, Li F, Robey RW and Schneider E . (2002). Cancer Res., 62, 5035–5045.

  • Volk EL, Rohde K, Rhee M, McGuire JJ, Doyle LA, Ross DD and Schneider E . (2000). Cancer Res., 60, 3514–3521.

  • Wang X, Shen F, Freisheim JH, Gentry LE and Ratnam M . (1992). Biochem. Pharmacol., 44, 1898–1901.

  • Wang Y, Zhao R, Russell RG and Goldman ID . (2001). Biochim. Biophys. Acta, 1513, 49–54.

  • Wang Y, Zhao R and Goldman ID . (2003). Biochem. Pharmacol., 65, 1163–1170.

  • Wang H, Zheng X, Behm FG and Ratnam M . (2000). Blood, 96, 3529–3536.

  • Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA and Shetty BV . (1996). Cancer Chemother. Pharmacol., 37, 509–517.

  • Wedge SR, Laohavinij S, Taylor GA, Boddy A, Calvert AH and Newell DR . (1995). Clin. Cancer Res., 1, 1479–1486.

  • Weitman SD, Frazier KM and Kamen BA . (1994). J. Neurooncol., 21, 107–112.

  • Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski Jr VR and Kamen BA . (1992a). Cancer Res., 52, 3396–3401.

  • Weitman SD, Weinberg AG, Coney LR, Zurawski Jr VR, Jennings DS and Kamen BA . (1992b). Cancer Res., 52, 6708–6711.

  • Welsh SJ, Titley J, Brunton L, Valenti M, Monaghan P, Jackman AL and Aherne GW . (2000). Clin. Cancer Res., 6, 2538–2546.

  • Werkheiser WC . (1961). J. Biol. Chem., 236, 888–893.

  • Westerhof GR, Jansen G, Van Emmerik N, Kathmann I, Rijksen G, Jackman AL and Schornagel JH . (1991). Cancer Res., 51, 5507–5513.

  • Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM and Jansen G . (1995). Mol. Pharmacol., 48, 459–471.

  • Whetstine JR, Gifford AJ, Witt T, Liu XY, Flatley RM, Norris M, Haber M, Taub JW, Ravindranath Y and Matherly LH . (2001). Clin. Cancer Res., 7, 3416–3422.

  • White JC . (1979). J. Biol. Chem., 254, 10889–10895.

  • White JC and Goldman ID . (1976). Mol. Pharmacol., 12, 711–719.

  • White JC and Goldman ID . (1981). J. Biol. Chem., 256, 5722–5727.

  • White JC, Loftfield S and Goldman ID . (1975). Mol. Pharmacol., 11, 287–297.

  • Whitehead VM . (1977). Cancer Res., 37, 408–412.

  • Whitehead VM, Payment C, Cooley L, Lauer SJ, Mahoney DH, Shuster JJ, Vuchich MJ, Bernstein ML, Look AT, Pullen DJ and Camitta B . (2001). Leukemia, 15, 1081–1088.

  • Whitehead VM, Rosenblatt DS, Vuchich MJ, Shuster JJ, Witte A and Beaulieu D . (1990). Blood, 76, 44–49.

  • Whitehead VM, Vuchich MJ, Cooley L, Lauer SJ, Mahoney DH, Shuster JJ, Payment C, Bernstein ML, Akabutu JJ, Bowen T, Kamen BA, Watson MS, Look AT, Pullen DJ and Camitta B . (1998a). Clin. Cancer Res., 4, 183–188.

  • Whitehead VM, Vuchich MJ, Cooley LD, Lauer SJ, Mahoney DH, Shuster JJ, Payment C, Koch PA, Akabutu JJ, Bowen T, Kamen BA, Ravindranath Y, Emami A, Look AT, Beardsley GP, Pullen DJ and Camitta B . (1998b). Leukemia Lymphoma, 31, 507–519.

  • Whitehead VM, Vuchich MJ, Lauer SJ, Mahoney D, Carroll AJ, Shuster JJ, Esseltine DW, Payment C, Look AT and Akabutu J . (1992). Blood, 80, 1316–1323.

  • Williams FMR and Flintoff WF . (1995). J. Biol. Chem., 270, 2987–2992.

  • Williams FMR, Murray RC, Underhill TM and Flintoff WF . (1994). J. Biol. Chem., 269, 5810–5816.

  • Wong SC, McQuade R, Proefke SA, Bhushan A and Matherly LH . (1997). Biochem. Pharmacol., 53, 199–206.

  • Wong SC, Proefke SA, Bhushan A and Matherly LH . (1995). J. Biol. Chem., 270, 17468–17475.

  • Wong SC, Zhang L, Witt TL, Proefke SA, Bhushan A and Matherly LH . (1999). J. Biol. Chem., 274, 10388–10394.

  • Worm J, Kirkin AF, Dzhandzhugazyan KN and Guldberg P . (2001). J. Biol. Chem., 276, 39990–40000.

  • Worzalla JF, Shih C and Schultz RM . (1998). Anticancer Res., 18, 3235–3239.

  • Wright JE, Vaidya CM, Chen Y and Rosowsky A . (2000). Biochem. Pharmacol., 60, 41–46.

  • Wu M, Fan J, Gunning W and Ratnam M . (1997). J. Membr. Biol., 159, 137–147.

  • Wu M, Gunning W and Ratnam M . (1999). Cancer Epidemiol. Biomarkers Prev., 8, 775–782.

  • Yalowich JC, Fry DW and Goldman ID . (1982). Cancer Res., 42, 3648–3653.

  • Yang C-H, Sirotnak FM and Dembo M . (1984). J. Membr. Biol., 79, 285–292.

  • Yang R, Sowers R, Mazza B, Healey JH, Huvos A, Grier H, Bernstein M, Beardsley GP, Krailo MD, Devidas M, Bertino JR, Meyers P and Gorlick R . (2003). Clin. Cancer Res., 9, 837–844.

  • Yu M and Melera PW . (1993). Cancer Res., 53, 6031–6035.

  • Zeng H, Chen ZS, Belinsky MG, Rea PA and Kruh GD . (2001). Cancer Res., 61, 7225–7232.

  • Zeng H, Liu G, Rea PA and Kruh GD . (2000). Cancer Res., 60, 4779–4784.

  • Zhang K and Rathod PK . (2002). Science, 296, 545–547.

  • Zhang L, Taub JW, Williamson M, Wong SC, Hukku B, Pullen J, Ravindranath Y and Matherly LH . (1998). Clin. Cancer Res., 4, 2169–2177.

  • Zhao R, Assaraf YG and Goldman ID . (1998a). J. Biol. Chem., 273, 19065–19071.

  • Zhao R, Assaraf YG and Goldman ID . (1998b). J. Biol. Chem., 373, 7873–7879.

  • Zhao R, Babani S, Gao F, Liu L and Goldman ID . (2000a). Clin. Cancer Res., 6, 3687–3695.

  • Zhao R, Gao F, Babani S and Goldman ID . (2000b). Clin. Cancer Res., 6, 3304–3311.

  • Zhao R, Gao F and Goldman ID . (1999a). Biochem. Pharmacol., 58, 1615–1624.

  • Zhao R, Gao F and Goldman ID . (2001). Biochem. Pharmacol., 61, 857–865.

  • Zhao R, Gao F and Goldman ID . (2002). Am. J. Physiol. Cell. Physiol., 282, C1512–C1517.

  • Zhao R, Gao F, Wang PJ and Goldman ID . (2000c). Mol. Pharmacol., 57, 317–323.

  • Zhao R, Gao F, Wang Y, Diaz GA, Gelb BD and Goldman ID . (2000d). J. Biol. Chem., 276, 1114–1118.

  • Zhao R, Seither R, Brigle KE, Sharina IG, Wang PJ and Goldman ID . (1997). J. Biol. Chem., 272, 21207–21212.

  • Zhao R, Sharina IG and Goldman ID . (1999b). Mol. Pharmacol., 56, 68–76.

  • Zhao R, Titus S, Gao F, Moran RG and Goldman ID . (2000e). J. Biol. Chem., 275, 26599–26606.

  • Zhao R, Wang Y, Gao F and Goldman ID . (2003). Biochim. Biophys. Acta, 1613, 49–56.

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Molecular, Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Rongbao Zhao & I David Goldman

Authors
  1. Rongbao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I David Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I David Goldman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, R., Goldman, I. Resistance to antifolates. Oncogene 22, 7431–7457 (2003). https://doi.org/10.1038/sj.onc.1206946

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206946

Keywords

This article is cited by

Search

Advanced search

Quick links