Skip to main content
SpringerLink
Log in

Multifunctional Modulators of Drug Resistance

  • Chapter
Drug Resistance

Part of the book series: Cancer Treatment and Research ((CTAR,volume 87))

  • 110 Accesses

Abstract

A variety of specific biochemical mechanisms have been identified that allow tumors to escape the cytotoxic effect of chemotherapy. Resistance may be induced to one particular class of cytotoxins, such as the resistance to methotrexate associated with a mutational change in the target enzyme dihydrofolate reductase. Resistance may also develop to a cross section of structurally unrelated classes of chemotherapy, such as the multidrug resistance (MDR) phenotype identified in the laboratories of Tsuruo [1], Biedler [2], and Ling [3].

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Tsuruo T (1989) Circumvention of drug resistance with calcium channel blockers and monoclonal antibodies. Cancer Treat Res 48:73–95.

    PubMed  CAS  Google Scholar 

  2. Biedler J (1994) Drug resistance: genotype versus phenotype—Thiry-second G.H.A. Clowes memorial lecture. Cancer Res 54:666–678.

    PubMed  CAS  Google Scholar 

  3. Childs S, Ling V (1994) The MDR superfamily of genes and its biological implications. In VT DeVita Jr, S Hellman, SA Rosenberg, eds. Important Advances in Oncology. Philadelphia: J.B. Lippincott Co:21–36.

    Google Scholar 

  4. Goodnight J, Mischak H, Mushinski JF (1994) Selective involvement of protein kinase C isozymes in differentiation and neoplastic transformation. Adv Cancer Res 64:159–209.

    PubMed  CAS  Google Scholar 

  5. Nishizuka Y (1986) Studies and perspectives of protein kinase C. Science 233:305–312.

    PubMed  CAS  Google Scholar 

  6. Nishizuka Y (1992) Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–613.

    PubMed  CAS  Google Scholar 

  7. Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334:661–665.

    PubMed  CAS  Google Scholar 

  8. Bradshaw T, Gescher A, Pettit GR (1992) Modulation by staurosporine of phorbol-ester-induced effects on growth and protein kinase C localization in A549 human lung-carcinoma cells. Int J Cancer 51:144–148.

    PubMed  CAS  Google Scholar 

  9. Niedel JE, Kuhn L, Vanderbark GR (1983) Phorbol diester receptor copurifies with protein kinase C. Proc Natl Acad Sci (USA) 80:36–40.

    CAS  Google Scholar 

  10. O’Brian CA, Ward NE, Gravitt KR, Fan D (1994) The role of protein kinase C in multidrug resistance. In LJ Goldstein, RF Ozols, eds. Anticancer drug resistance: advances in molecular and clinical research. Norwell, MA: Kluwer Academic Publishers: 41–55.

    Google Scholar 

  11. Chambers TC, Chalikonda I, Eilon G (1990) Correlation of protein kinase C translocation, P-glycoprotein phosphorylation and reduced drug accumulation in multidrug resistant human KB cells. Biochem Biophys Res Comm 169:253–259.

    PubMed  CAS  Google Scholar 

  12. Ma L, Marquardt D, Takemoto L, Center M (1991) Analysis of P-glycoprotein phosphorylatoin in HL 60 cells isolated for resistance to vincristine. J Biol Chem 266:5593–5599.

    PubMed  CAS  Google Scholar 

  13. Aquino A, Warren BS, Omichinski J, Hartman KD, Glazer RI (1990) Protein Kinase C-γ present in adriamycin resistant HL-60 leukemia cells. Biochem Biophys Res Commun 166:723–728.

    PubMed  CAS  Google Scholar 

  14. Lee S, Karaszkiewicz J, Anderson WB (1992) Elevated level of nuclear protein kinase C in multidrug-resistant MCF-7 human breast carcinoma cells. Cancer Res 52:3750–3759.

    PubMed  CAS  Google Scholar 

  15. Sugawara S, Kumano N, Saijo Y, Suzuki S, Numata Y, Sato G, Motomiya M (1992) Protein kinase C activity in human leukemia cell lines with reference to sensitivity to antineoplastic agents. Tohoku J Exp Med 168:393–396.

    PubMed  CAS  Google Scholar 

  16. Blobe GC, Sachs CW, Khan WA, Fabbro D, Stabel S, Wetsel WC, Obeid LM, Fine RL, Hannun YA (1993) Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistance MCF-7 cells. J Biol Chem 268:658–664.

    PubMed  CAS  Google Scholar 

  17. Yu G, Ahmad S, Aquino A, Fairchild C, Trepel JB, Ohno S, Suzuki K, Tsuruo T, Cowan KH, Glazer RI (1991) Transfection with protein kinase C-(X confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein. Cancer Comm 3:181–189.

    CAS  Google Scholar 

  18. Ahmad S, Trepel JB, Ohno S, Suzuki K, Tsuruo T, Glazer RI (1992) Role of protein kinase C in the modulation of multidrug resistance: expression of the atypical γ isoform of protein kinase C does not confer increased resistance to doxorubicin. Mol Pharmacol 42:1004–1009.

    PubMed  CAS  Google Scholar 

  19. Chaudhary P, Roninson I (1992) Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists. Oncol Res 4:281–290.

    PubMed  CAS  Google Scholar 

  20. Ferguson PJ, Cheng Y-c (1987) Transient protection of cultured human cells against antitumor agents by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 47:433–441.

    PubMed  CAS  Google Scholar 

  21. Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA 85:582–586.

    PubMed  CAS  Google Scholar 

  22. O’Brian C, Fan D, Ward N, Dong Z, Iwamoto L, Gupta K, Earnest L, Fidler I (1991) Transient enhancement of multidrug resistance by the bile acid deoxycholate in murine fibrosarcoma cells in vitro. Biochem Pharmacol 41:797–806.

    PubMed  Google Scholar 

  23. Takeda Y, Nishio K, Sugimoto Y, Kasahara K, Kubo S, Fujiwara Y, Niitani H, Saijo N (1991) Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12–O-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance. Int J Cancer 48:931–937.

    PubMed  CAS  Google Scholar 

  24. Fan D, Fidler IJ, Ward N, Seid C, Earnest LE, Housey GM, O’Brian CA (1992) Stable expression of a cDNA encoding rat brain protein kinase C-βI confers a multidrug-resistant phenotype on rat fibroblasts. Cancer Res 52:661–668.

    Google Scholar 

  25. Banfi P, Parolini O, Lanzi C, Gambetta A (1992) Lipid peroxidation, phosphoinositide turnover and protein kinase C activation in humor platelets treated with anthracyclines and their complexes with Fe(III). Biochem Pharmacol 43:1521–1527.

    PubMed  CAS  Google Scholar 

  26. Lanzi C, Gambetta RA, Perego P, Banfi P, Franzi A, Guazzoni L, Zunino F (1991) Protein kinase C activation by anthracyclines in swiss 3t3 cells. Int J Cancer 47:136–142.

    PubMed  CAS  Google Scholar 

  27. Palayoor S, Stein JM, Hait WN (1987) Inhibition of protein kinase C by antineoplastic agents implications for drug resistance. Biochem Biophys Res Comm 148:718–725.

    PubMed  CAS  Google Scholar 

  28. Rubin E, Kharbanda S, Gunji H, Weichselbaum R, Kufe D (1992) cis-Diamminedichloroplatinum (II) induces c-jun expression in human myloid leukemia cells: potential involement of a protein kinase c-dependent signaling pathway. Cancer Res 52:878–882.

    PubMed  Google Scholar 

  29. Goode N, Hughes K, Woodgett JR, Parker PJ (1992) Differential regulation of glycogen synthase kinase-3β by protein kinase C isotypes. J Biol Chem 267:16878–16882.

    PubMed  CAS  Google Scholar 

  30. Basu A, Teicher BA, Lazo JS (1990) Involvement of protein kinase C in phorbol ester-induced sensitization of HeLa cells to cis-diamminedichloroplatinum (II). J Biol Chem 265:8451–8457.

    PubMed  CAS  Google Scholar 

  31. Basu A, Kozikowski AP, Sato K, Lazo JS (1991) Cellular sensitization to cis-diamminedichloroplatinum (II) by novel analogues of the protein kinase C activator lyngbyatoxin a. Cancer Res 51:2511–2514.

    PubMed  CAS  Google Scholar 

  32. Basu A, Lazo JS (1992) Sensitization of human cervical carcinoma cells to cis-diamminedichloroplatinum (II) by bryostatin 1. Cancer Res 52:3119–3124.

    PubMed  CAS  Google Scholar 

  33. Basu A, Evans RW (1994) Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis-diamminedichloroplatinum (II). Int J Cancer 58:587–591.

    PubMed  CAS  Google Scholar 

  34. Fan Z, Balsega J, Masui H, Mendelsohn J (1993) Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well establishede A431 cell xenografts. Cancer Res 53:4673–4642.

    Google Scholar 

  35. Schlessinger J (1986) Allosteric regulation of the epidermal growth factor receptor kinase. J Cell Biol 103:2067–2072.

    PubMed  CAS  Google Scholar 

  36. Hofmann J, Doppler W, Jakob A, Maly K, Posch L, Uberall F, Grunicke HH (1988) Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum (ii) and nitrogen mustard by inhibitors of protein kinase c. Int J Cancer 42:382–388.

    PubMed  CAS  Google Scholar 

  37. Hofmann J, Fiebig H, Winterhalter BR, Berger DR, Grunicke H (1990) Enhancement of the anti-proliferative activity of cis-diamminedichloroplatinum (ii) by quercetin. Int J Cancer 45:536–539.

    PubMed  CAS  Google Scholar 

  38. Perego P, Casati G, Gambetta RA, Soranzo C, Zunino F (1993) Effect of modulation of protein kinase C activity on cisplatin cytotoxicity in cisplatin-resistant and cisplatin-sensitive human osteosarcoma cells. Cancer Lett 72:53–58.

    PubMed  CAS  Google Scholar 

  39. Grant S, Jarvis WD, Swerlow PS, Turner AJ, Traylor RS, Wallace HJ, Lin P-s, Pettit GR, Gewirtz DA (1992) Potentiation of the activity of 1-β-D-arabinofuranosylcytosine by the protein kinase C activator bryostatin 1 in HL-60 cells: association with enhanced fragmentation ofmature DNA. Cancer Res 52:6270–6278.

    PubMed  CAS  Google Scholar 

  40. Jarvis WD, Povirk LF, Turner AJ, Traylor RS, Gewirtz DA, Pettit GR, Grant S (1994) Effects of bryostatin 1 and other pharmacological activators of protein kinase C on l-[beta-D-arabinofuranosyl]cytosine-induced apoptosis in HL-60 human promyelocytic leukemia cells. Biochem Pharmacol 47:839–852.

    PubMed  CAS  Google Scholar 

  41. Hocevar B, Fields A (1991) Selective translocation of βII- protein kinase c to the nucleus of human promyelocytic (HL60) leukemia cells. J Biol Chem 266:28–33.

    PubMed  CAS  Google Scholar 

  42. Dlugosz AA, Yuspa SH (1991) Staurosporine induces protein kinase C agonist effects and maturation of normal and neoplastic mouse keratinocytes in vitro. Cancer Res 51:4677–4684.

    PubMed  CAS  Google Scholar 

  43. Kennedy M, Prestigiacomo L, Tyler G, May W, Davidson N (1992) Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res 52:1278–1283.

    PubMed  CAS  Google Scholar 

  44. Stanwell C, Gescher A, Bradshaw TD, Pettit GR (1994) The role of protein kinase C isoenzymes in the growth inhibition caused by bryostatin 1 in human A549 lung and MCF-7 breast carcinoma cells. Int J Cancer 56:585–592.

    PubMed  CAS  Google Scholar 

  45. Basu A (1993) The potential of protein kinase C as a target for anticancer treatment. Pharmacol Ther 59:257–280.

    PubMed  CAS  Google Scholar 

  46. Pettit GR, Herald CL, Doubek DL, Herald DL (1982) Isolation and structure of bryostatin. J Amer Chem Soc 104:6846–6848.

    CAS  Google Scholar 

  47. Hornung RL, Pearson JW, Beckwith M, Longo DL (1992) Preclinical evaluation of bryostatin as an anticancer agent against several murine tumour cell lines: in vitro versus in vivo activity. Cancer Res 52:101–107.

    PubMed  CAS  Google Scholar 

  48. Schuchter LM, Esa AH, May WS, Laulis MK, Pettit GR, Hess AD (1991) Successful treatment of murine melanoma with bryostatin 1. Cancer Res 51:682–687.

    PubMed  CAS  Google Scholar 

  49. Kraft AS, Smith JB, Berkow RL (1986) Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc Nat Acad Sci USA 83:1334–1338.

    PubMed  CAS  Google Scholar 

  50. Kazanietz MG, Lewin NE, Gao F, Pettit GR, Blumberg PM (1994) Binding of [26-3H] bryostatin 1 and analogs to calcium-dependent and calcium-independent protein kinase C isozymes. Mol Pharmacol 46:374–379.

    PubMed  CAS  Google Scholar 

  51. Stone RM, Sariban E, Pettit GR, Kufe DW (1988) Bryostatin 1 activates protein kinase C and induces monocytic differentiation in HL-60 cells. Blood 72:208–213.

    PubMed  CAS  Google Scholar 

  52. Dale IL, Bradshaw TD, Gescher A, Pettit GR (1989) Comparison of effects of bryostatins 1 and 2 and 12-0-tetradecanoylphorbol-13-acetate on protein kinase C activity in A549 human lung carcinoma cells. Cancer Res 49:3242–3245.

    PubMed  CAS  Google Scholar 

  53. Isakov N, Galron D, Mustelin T, Pettit GR, Altman A (1993) Inhibition of phorbol ester-induced T cell proliferation by bryostatin is associated with rapid degradation of protein kinase C. J Immunol 150:1195–1204.

    PubMed  CAS  Google Scholar 

  54. Li F, Grant S, Pettit GR, McCrady CW (1992) Bryostatin 1 modulates the proliferation and lineage commitment of human myeloid progenitor cells exposed to recombinant interleukin-3 and recombinant granulocyte-macrophage colony-stimulating factor. Blood 80:2495–2502.

    PubMed  CAS  Google Scholar 

  55. Tuttle TM, Inge TH, Bethke KP, McCrady CW, Pettit GR, Bear HD (1992) Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1. Cancer Res 52:548–553.

    PubMed  CAS  Google Scholar 

  56. Kraft AS, William F, Pettit GR, Lilly MB (1989) Varied differentiation responses of human leukemias to brryostatin 1. Cancer Res 49:1287–1293.

    PubMed  CAS  Google Scholar 

  57. Mohammad RM, Al-Katib A, Pettit GR, Sensenbrenner LL (1993) Differential effects of bryostatin 1 on human non-Hodgkin’s B-lymphoma cell lines. Leuk Res 17:1–8.

    PubMed  CAS  Google Scholar 

  58. Patella V, Casolaro V, Ciccarelli A, Pettit GR, Culumbo M, Marone G (1995) The antineoplastic bryostatins affect human basophils and mast cells differently. Blood 85:1272–1281.

    PubMed  CAS  Google Scholar 

  59. Berkow RL, Schlabach L, Dodson R, Benjamin Jr WH, Pettit GR, Rustagi P, Kraft AS (1993) In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. Cancer Res 53:2810–2815.

    PubMed  CAS  Google Scholar 

  60. Grant S, Jarvis WD, Turner AJ, Wallace HJ, Pettit GR (1992) Effects of bryostatin 1 and rGM-CSF on the metabolism of 1-B-D-arabinofuranosylcytosine in human leukemic myeloblasts. Br J Haematol 82:522–528.

    PubMed  CAS  Google Scholar 

  61. Pommier Y, Kerrrigan D, Hartman KD, Glazer RI (1990) Phosphorylation of mammalian dna topoisomerase I and activation by protein kinase C. J Biol Chem 265:9418–9422.

    PubMed  CAS  Google Scholar 

  62. Yalowich JC, Ritke MK, Allan WP, Murray NR, Fields AP (1995) Bryostatin 1 upregulates topoisomerase II phosphorylation and potentiates VP16 activity in VP-16 resistant K562 cells. Proc Amer Assoc Cancer Res 36:342 (abstr).

    Google Scholar 

  63. Philip PA, Rea D, Thavasu P, Carmichael J, Stuart NSA, Rockett H, Talbot DC, Ganesan T, Pettit GR, Balkwill F, Harris AL (1993) Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee [see comments]. J Natl Cancer Inst 85:1812–1818.

    PubMed  CAS  Google Scholar 

  64. Prendiville J, Crowther D, Thatcher N, Woll PJ, Fox BW, McGown A, Testa N, Stern P, McDermott R, Potter M, Pettit GR (1993) A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br J Cancer 68:418–425.

    PubMed  CAS  Google Scholar 

  65. Brinkmeier H, Jockusch H (1987) Activators of protein kinase C induce myotonia by lowering chloride conductance in muscle. Biochem Biophys Res Commun 148:1283–1289.

    Google Scholar 

  66. Scheid C, Prendiville J, Jayson G, Crowther D, Fox B, Pettit GR, Stern PL (1994) Immunomodulation in patients receiving intravenous Bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro. Cancer Immunol Immunother 39:223–30.

    PubMed  CAS  Google Scholar 

  67. David NA, Burgner PR (1956) Antibiot. Med 2:219.

    PubMed  CAS  Google Scholar 

  68. Hinman JW, Caron EL, Hoeksema H (1957) The structure of novobiocin. J Amer Chem Soc 79:3789–3800.

    CAS  Google Scholar 

  69. Barrett-Bee K, Pinder P (1994) The accumulation of novobiocin by Escherichia coli and Staphilococcus aureus. J Antimicrobial Chemother 33:1165–1171.

    CAS  Google Scholar 

  70. Drlica K, Franco RJ (1988) Inhibitors of DNA topoisomerases. Biochemistry 27:2253–2259.

    PubMed  CAS  Google Scholar 

  71. Fox N, Studzinski GP (1982) DNA dependence and inhibition by novobiocin and coumermycin of the nucleolar adenosine triphosphatase (ATPase) of human fibroblasts. J Histochem Cytochem 30:364–370.

    PubMed  CAS  Google Scholar 

  72. Geliert M (1981) DNA topoisomerases. Ann Rev Biochem 50:879–910.

    Google Scholar 

  73. Cotten M, Bresnahan D, Thompson S, Chalkli R (1986) Novobiocin precipitates histones at concentrations normally used to inhibit eukaryotic type II topoisomerase. Nucl Acids Res 14:3671–3686.

    PubMed  CAS  Google Scholar 

  74. Downes CS, Ord MJ, Mulligan AM, Collins ARS (1985) Novobiocin inhibition of DNA excision repair may occur through effects on mitochondrial structure and ATP metabolism, not on repair topoisomerases. Carcinogenesis 6:1343–1352.

    PubMed  CAS  Google Scholar 

  75. Gottesfeld JM (1986) Novobiocin inhibits RNA polymerase III transcription in vitro by a mechanism distinct from topoisomerase II. Nucl Acids Res 14:2075–2088.

    PubMed  CAS  Google Scholar 

  76. Constantinou A, Henning-Chubb C, Huberman E (1989) Novobiocin and phorbol 12-myristate 13-acetate-induced differentiation of human leukemia cells associated with a reduction in topoisomerase II activity. Cancer Res 49:1110–1117.

    PubMed  CAS  Google Scholar 

  77. Nordenberg J, Albukrek D, Hadar T, Fux A, Wasserman L, Novogrodsky A, Sidi Y (1992) Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16. Brit J Cancer 65:183–188.

    PubMed  CAS  Google Scholar 

  78. Rappa G, Lorico A, Sartorelli AC (1990) Induction of the differentiation of WEHI-3B D+ monomyelocytic leukemic cells by inhibitors of topoisomerase II. Cancer Res 50:6723–6730.

    PubMed  CAS  Google Scholar 

  79. Rius C, Zorrilla AR, Cabanas C, Mata F, Bernabeu C (1991) Differentiation of human promonocytic leukemia U-937 cells with DNA topisomerase II inhibitors: induction of vimentin gene expression. Mol Pharmacol 39:442–448.

    PubMed  CAS  Google Scholar 

  80. Eder JP, Teicher BA, Holden SA, Cathcart KNS, Schnipper LE (1987) Novobiocin enhances alkylating agent cytotoxicity and DNA interstrand crosslinks in a murine model. J Clin Invest 79:1524–1528.

    PubMed  CAS  Google Scholar 

  81. Eder JP, Teicher BA, Holden SA, Cathcart KNS, Schnipper LE, Frei EI (1989) Effects of novobiocin on the antitumor activity and tumor cell and bone marrow survivals of three alkylating agents. Cancer Res 49:595–598.

    PubMed  CAS  Google Scholar 

  82. Eder JP, Wheeler CA, Teicher BA, Schnipper LE (1991) A phase I clinical trial of novobiocin, a modulator of alkylating agent cytotoxicity. Cancer Res 51:510–513.

    PubMed  CAS  Google Scholar 

  83. Kennedy MJ, Armstrong DK, Huelskamp A, Ohly K, Clarke BV, Colvin OM, Grochow B, Chen T-L, Davidson NE (1995) Phase I and pharmacologic study of the alkylating agent modulator Novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer. J Clin Oncol 13:1136–1143.

    PubMed  CAS  Google Scholar 

  84. Ellis GK, Crowley J, Livingston RB, Goodwin JW, Hutchins L, Allen A (1991) Cisplatin and novobiocin in the treatment of non-small-cell lung cancer. A Southwest Oncology Group Study. Cancer 67:2969–2973.

    PubMed  CAS  Google Scholar 

  85. Schwartz GN, Teicher BA, Eder JP Jr, Korbut T, Holden SA, Arra G, Herman TS (1993) Modulation of antitumor alkylating agents by novobiocin, topotecan, and lonidamine. Cancer Chemother Pharmacol 32:455–462.

    PubMed  CAS  Google Scholar 

  86. Rappa G, Lorico A, Sartorelli AC (1992) Potentiation by novobiocin of the cytotoxic activity of etoposide (VP-16) and teniposide (VM-26). Int J Cancer 51:780–787.

    PubMed  CAS  Google Scholar 

  87. Rappa G, Lorico A, Sartorelli AC (1993) Reversal of etoposide resistance in non-P-glycoprotein expressing multidrug resistant tumor cell lines by novobiocin. Cancer Res 53:5487–5493.

    PubMed  CAS  Google Scholar 

  88. Lorico A, Rappa G, Sartorelli AC (1992) Novobiocin-induced accumulation of etoposide (VP-16) in WEHI-3B D+ leukemia cells. Int J Cancer 52:903–909.

    PubMed  CAS  Google Scholar 

  89. Yang JM, Hait WN (1991) Use of multidrug resistant L1210 cell line for in vitro and in vivo drug screenig. Proc Am Assoc Cancer Res (abstr) 32:364.

    Google Scholar 

  90. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992) Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line. Science 258:1650–1654.

    PubMed  CAS  Google Scholar 

  91. Yalowich JC, Ross WE (1985) Verapamil-induced augmentation of etoposide accumulation in L1210 cells in vitro. Cancer Res 47:1010–1015.

    Google Scholar 

  92. Ozols RF, Cunnion RE, Klecker RW Jr, Hamilton TC, Ostchega Y, Parrillo JE, Young RC (1987) Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol 5:641–647.

    PubMed  CAS  Google Scholar 

  93. Akiyama SI, Fojo A, Hanover JA, Pastan I, Gottesman MM (1985) Isolation and genetic char-acterizaion of human KB cell lines resistant to multiple drugs. Somatic Cell Mol Genet 11:117–126.

    CAS  Google Scholar 

  94. Ford JM, Bruggemann EP, Pastan I, Gottesman MM, Hait WN (1990) Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. Cancer Res 50:1748–1756.

    PubMed  CAS  Google Scholar 

  95. Van der Graaf WTA, De Vries EGE, Uges DRA, Nanninga AG, Meijer C, Vellenga E, Mulder POM, Mulder NH (1991) In vitro and in vivo modulation of multi-drug resistance with amiodarone. Int J Cancer 48:616–622

    PubMed  Google Scholar 

  96. Rappa G, Lorico A, Murren JR, Anderson S, Sartorelli AC (1995) Clinical evaluation of the modulation of the antitumor activity of VP-16 by novobiocin (Novo) in human tumors. Proc Am Assoc Cancer Res 36:291.

    Google Scholar 

  97. Willson JKV, Fischer PH, Tutsch K, Alberti D, Simon K, Hamilton RD, Bruggink J, Koeller JM, Tormey DC, Earhart RH, Ranhosky A, Trump DL (1988) Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage. Cancer Res 48:5585–5590.

    PubMed  CAS  Google Scholar 

  98. Willson JKV, Fischer PH, Remick SC, Tutsch KD, Grem JL, Nieting L, Alberti D, Bruggink J, Trump DL (1989) Methotrexate and dipyridamole combination chemotherapy based upon inhibition of nucleoside salvage in humans. Cancer Res 49:1866–1870.

    PubMed  CAS  Google Scholar 

  99. Chan T, Howell S (1985) Mechanism of synergy between N-phospphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line. Cancer Res 45:3598–3604

    PubMed  CAS  Google Scholar 

  100. Remick SC, Grem JL, Fischer PH, Tutsch KD, Alberti DB, Nieting LM, Tombes MB, Bruggink J, Willson JKV, Trump DL (1990) Phase I trial of 5-fluorouracil and dipyridamole administered by seventy-two-hour concurrent continuous infusion. Cancer Res 50:2667–2672.

    PubMed  CAS  Google Scholar 

  101. Grem JL, Fischer PH (1989) Enhancement of 5-fluorouracil’s anticancer activity by dipyridamole. Pharmacol Ther 40:349–371.

    PubMed  CAS  Google Scholar 

  102. Weber G (1983) Biochemical strategy of cancer cells and the design of chemotherapy. Cancer Res 43:3466–3492.

    PubMed  CAS  Google Scholar 

  103. Grem J, Fischer H (1986) Alteration of fluorouracil metabolism in human colon cancer cells by dipyridamole with a selective increase in fluorodeoxyuridine monophosphate levels. Cancer Res 46:6191–6199.

    PubMed  CAS  Google Scholar 

  104. Isonishi S, Kirmani S, Kim S, Plaxe SC, Braly PS, McClay EF, Howell SB (1991) Phase I and pharmacokinetic trial of intraperitoneal etoposide in combination with the multidrug-resistance-modulating agent dipyridamole. J Natl Cancer inst 83:621–626.

    PubMed  CAS  Google Scholar 

  105. Bailey H, Wilding G, Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB, Grem JL, Spriggs DR (1992) A phase I trial of 5-fluorouracil, leucovorin, and dipyridamole given by concurrent 120-h continuous infusions. Cancer Chemother Pharmacol 30:297–302.

    PubMed  CAS  Google Scholar 

  106. Budd GT, Jayaraj A, Grabowski D, Adelstein D, Bauer L, Boyett J, Bukowski R, Murthy S, Weick J (1990) Phase I trial of dipyridamole with 5-fluorouracil and folinic acid. Cancer Res 50:7206–7211.

    PubMed  CAS  Google Scholar 

  107. Buzaid AC, Alberts DS, Einspahr J, Mosley K, Peng Y-M, Tutsch K, Spears CP, Garewal HS (1989) Effect of dipyridamole on fluorodeoxyuridine cytotocicity in vitro and in cancer patients. Cancer Chemother. Pharmacol 25:124–130.

    CAS  Google Scholar 

  108. Grem JL, Fischer PH (1985) Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells by dipyridamole. Cancer Res 45:2967–2972.

    PubMed  CAS  Google Scholar 

  109. Howell SB, Hom DK, Sanga R, Vick JS, Chan TCK (1989) Dipyridamole enhancement of etoposide sensitivity. Cancer Res 49:4147–4153.

    PubMed  CAS  Google Scholar 

  110. Kusumoto H, Maehara Y, Anai H, Kumashiro R, Sugimachi K (1991) Dipyridamole potentiates adriamycin cytotoxicity by a mechanism other than inhibiting nucleoside uptake. Anticancer Res 11:1539–1542.

    PubMed  CAS  Google Scholar 

  111. Jekunen A, Vick J, Sanga R, Chan TCK, Howell SB (1992) Synergism between dipyridamole and cisplatin in human carcinoma cells in vitro. Cancer Res 52:3566–3571.

    PubMed  CAS  Google Scholar 

  112. Kusumoto H, Maehara Y, Anai H, Kusumoto T, Sugimachi K (1988) Potentiation of adriamycin cytotoxicity by dippyridamole against HeLa cells in vitro and sarcoma 180 cells in vivo. Cancer Res 48:1208–1212.

    PubMed  CAS  Google Scholar 

  113. Damle BD, Sridhar R, Desai PB (1994) Dipyridamole modulates multidrug resistance and intracellular as well as nuclear levels of doxorubicin in B16 melanoma cells. Int J Cancer 56:113–118.

    PubMed  CAS  Google Scholar 

  114. Howell SB, Hom D, Sanga R, Vick JS, Abramson IS (1989) Comparison of the synergistic potentiation of etoposide, doxorubicin, and vinblastine cytotoxicity by dipyridamole. Cancer Res 49:3178–3183.

    PubMed  CAS  Google Scholar 

  115. Hirose M, Takeda E, Ninomiya T, Kuroda Y, Miyao M (1987) Synergistic inhibitory effects of dipyridamole and vincristine on the growth of human leukaemia and lymphoma cells. Br J Cancer 56:413–417.

    PubMed  CAS  Google Scholar 

  116. Ford JM, Prozialeck WC, Hait WN (1989) Structural features determining activity of phenothia-zines and related drugs for inibition of cell growth and reversal of multidrug resistance. Mol Pharmacol 35:105–115.

    PubMed  CAS  Google Scholar 

  117. Shalinsky DR, Andreeff M, Howell SB (1990) Modulation of drug sensitivity by dipyridamole in multidrug resistant cells in vitro. Cancer Res 50:7573–7543.

    Google Scholar 

  118. Goel R, Cleary SM, Horton C, Balis FM, Zimm S, Kirmani S, Howell SB (1989) Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole. J Clin Oncol 7:262–269.

    PubMed  CAS  Google Scholar 

  119. Ramu N, Ramu A (1989) Circumvention of adriamycin resistance by dipyridamole analogues: a structure-activity relationship study. Int J Cancer 43:487–491.

    PubMed  CAS  Google Scholar 

  120. Chen H-x, Bamberger U, Heckel A, Guo X, Cheng Y-c (1993) BIBW 22, a dipyridamole analogue, acts as a bifunctional modulator on tumor cells by influencing both P-glycoprotein and nucleoside transport. Cancer Res 53:1974–1977.

    PubMed  CAS  Google Scholar 

  121. Gaj CL, Anyanwutaku IO, Cole SC, Chang Y, Cheng Y-c (1995) Reversal of multidrug resistance associated protein mediated multidrug resistance in human carcinoma cell lines by the l/enatiomer of verapamil. Proc Amer Assoc Cancer Res 36:346 (abstr).

    Google Scholar 

  122. Chen H-x, Rhee DK, Heckel A, Bamberger U, Cheng Y-c (1994) Biochemical studies of BIBW 22, a bifunctional modulator for nucleoside transport and p-glycoprotein function. Proc Amer Assoc Cancer Res 35:361 (abstr).

    Google Scholar 

  123. Chen H-x, Bamberger U, Heckel A, Rhee D, Cheng Y-c (1995) Differential mechanisms of BIBW 22 in modulating multidrug-resistant phenotype and in inhibiting nucleoside transport. Proc Amer Assoc Cancer Res 36:372 (abstr).

    Google Scholar 

  124. Boven E, Jansen W, Van Telligen O, Beijnen J, Pinedo H (1995) Modulation of vincristine (VCR) concentrations by dexnigulpine or BIBW22S in tissues of tumor-bearing mice. Proc Amer Assoc Cancer Res 36:341 (abstr).

    Google Scholar 

  125. Jansen WJM, Pinedo HM, Kuiper CM, Lincke C, Bamberger U, Heckel A, Boven E (1994) Biochemical modulation of “classical” multidrug resistance by BIBW22S, a potent derivative of dipyridamole. Ann Oncol 5:733–739.

    PubMed  CAS  Google Scholar 

  126. Karpatkin S, Pearlstein E (1981) Role of platelets in tumor cell metastases. Ann Int Med 95:636–641.

    PubMed  CAS  Google Scholar 

  127. Sakaguchi Y, Emi Y, Maehara Y, Kohnoe S, Sugimachi K (1990) Combined treatment of adriamycin and dipyridamole inhibits lung metastasis of B16 melanoma cells in mice. Eur Surg Res 22:213–218.

    PubMed  CAS  Google Scholar 

  128. Tzanakakis GN, Agarwal KC, Vezeridis MP (1992) Prevention of human pancreatic cancer cell induced hepatic metastasis in nude mice by dipyridamole and its analog RA-233. Cancer 71:2466–2471.

    Google Scholar 

  129. Floridi A, Paggi MG, Marcante ML, Silvestrini B, Caputo A, De Martino C (1981) Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells. J Natl Cancer Inst 66:497–499.

    PubMed  CAS  Google Scholar 

  130. Floridi A, Paggi MC, D’Atri S, De Martino C, Marcante ML, Silvestrini B, Caputo A (1981) Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells. Cancer Res 41:4661–4666.

    PubMed  CAS  Google Scholar 

  131. Arancia G, Malorni W, Crateri Trovalusci P, Isacchi G, Giannella G, De Martino C (1988) Differential effect of lonidamine on the plasma membrane of normal and leukemic human lymphocytes. Exper Mol Pathol 48:37–47.

    CAS  Google Scholar 

  132. De Martino C, Malorni W, Accinni L, Rosati F, Nista A, Formisano G, Silvestrini B, Arancia G (1987) Cell membrane changes induced by lonidamine in human erythrocytes and T lymphocytes, and Ehrlich ascites tumor cells. Exp Mol Pathol 46:15–30.

    PubMed  Google Scholar 

  133. Teicher BA, Herman TS, Hoden SA, Epelbaum R, Liu S, Frei E (1991) Lonidamine as a modulator of alkylating agent activity in vitro and in vivo. Cancer Res 51:780–784.

    PubMed  CAS  Google Scholar 

  134. Hahn GM, van Kersen I, Silverstrini B (1984) Inhibition of the recovery from potentially lethal damage by lonidamine. Br J Cancer 50:657–660.

    PubMed  CAS  Google Scholar 

  135. Kim JH, Alfieri AA, Kim SH, Young CW (1986) Potentiation of radiation effects on two murine tumors by lonidamine. Cancer Res 46:1120–1123.

    PubMed  CAS  Google Scholar 

  136. Raaphorst GP, Feeley MM, Heller DP, Danjoux CE, Martin L, Maroun JA, De Sanctis AJ (1990) Lonidamine can enhance the cytotoxic effect of cisplatin in human tumour cells and rodent cells. Anticancer Res 10:923–928.

    PubMed  CAS  Google Scholar 

  137. Zupi G, Greco C, Laudonio N, Benassi M, Silvestrini B, Caputo A (1986) In vitro and in vivo potentiation by lonidamine of the antitumor effect to adriamycin. Anticancer Res 6:1245–1250.

    PubMed  CAS  Google Scholar 

  138. Kaplan O, Navon G, Lyon RC, Faustino PJ, Straka EJ, Cohen JS (1990) Effects of 2-deoxyglucose on drug sensitive and drug resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism. Cancer Res 50:544–551.

    PubMed  CAS  Google Scholar 

  139. Citro G, Cucco C, Verdina A, Zupi G (1991) Reversal of adriamycin resistance by lonidamine in a human breast cancer cell line. Br J Cancer 64:534–536.

    PubMed  CAS  Google Scholar 

  140. Band PR, Maroun J, Pritchard K, Stewart D, Coppin CM, Wilson K, Eisenhauer EA (1986) Phase II study of lonidamine in patients with metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group Study. Cancer Treat Rep 70:1305–1310.

    PubMed  CAS  Google Scholar 

  141. Robustelli della Cuna G, Pedrazzoli P (1991) Toxicity and clinical tolerance of lonidamine. Semin Oncol 18 (Suppl 4):18–22.

    PubMed  CAS  Google Scholar 

  142. Murray N, Shah A, Band P (1987) Phase II study of lonidamine in patients with small cell carcinoma of the lung. Cancer Treat Rep 71:1283–1284.

    PubMed  CAS  Google Scholar 

  143. Pronzato P, Amoroso D, Bertelli G, Conte PF, Cusimano MP, Ciottoli GB, Gulisano M, Lionetto R, Rosso R (1989) Phase II study of lonidamine in metastatic breast cancer. Br J Cancer 59:251–253.

    PubMed  CAS  Google Scholar 

  144. Robins HI, Neuberg DS, Benson AB, Pandya KJ, Tormey DC (1990) Phase II study of lonidamine in patients with metastatic breast cancer. Invest New Drugs 8:397–399.

    PubMed  CAS  Google Scholar 

  145. Weinerman BH, Eisenhauer EA, Besner JG, Coppin CM, Stewart D, Band PR (1986) Phase II trial of lonidamine in patients with metastatic renal cell carcinoma. A National Cancer Institute of Canada Clinical Trial Group Study. Cancer 70:751–754.

    CAS  Google Scholar 

  146. Dogliotti L, Berruti A, Buniva T, Zola P, Bau MG, Farris A, Sarobba MG, Bottini A, Arquati P, Deltetto F, Gosso P, Monzeglio C, Moro G, Sussio M, Perroni D (1994) High-dose epirubicin vs high-dose epirubicin + lonidamine in advanced breast cancer. Proc Amer Soc Clin Oncol 13:58 (abstr).

    Google Scholar 

  147. Dogliotti L, Berruti A, Buniva T, Zola P, Bau MG, Farris A, Sarobba MG, Bottini A, Arquati P, Deltetto F, Gosso P, Monzeglio C, Moro G, Sussio M, Perroni D (1994) A randomized comparison of high dose epirubicin versus high dose epirubicin plus lonidamine in advanced breast cancer patients. First results from a cooperative group study. Int J Oncol 4:747–752.

    Google Scholar 

  148. Calabresi F, Marolla P, Di Lauro L, Curcio CG, Paoletti G, Lombardi A, Giannarelli D, Ballatore P, Foggi C, Di Palma M, Stolfi R, Cortesi E (1994) Lonidamine as a potentiating agent of the FAC regimen in the treatment of advanced breast cancer. Results of a multicentric clinical study. Int J Oncol 4:753–760.

    Google Scholar 

  149. Calabresi F (1994) Drug resistance: lonidamine. Principles & Prac. Oncol PPO Updates 8:1–15.

    Google Scholar 

  150. Lorusso V, Catino A, Brandi M, Piano A, Palomba G, Forcignano R, Mazzotta S, Musca F, Serravezza G, Durini E, Contillo A, Pezzella G, Pallazzo S, Chetri C, De Lena M (1994) Cyclophosphamide, mitoxantrone and fluorouracil versus Cyclophosphamide, mitoxantrone and fluorouracil plus lonidamine for the treatment of advanced breast cancer. A multicentric randomized clinical trial. Int J Oncol 4:767–772.

    Google Scholar 

  151. Pacini P, Algeri R, Rinaldini M, Guarnieri A, Bastiani P, Barsanti G, Neri B, Marzano S, Tucci E (1994) FEC (fluorouracil, epirubicin and cyclophosphamide) versus EM (epirubicin and mitomycin-C) with or without lonidamine as first line treatment for advanced breast cancer. A multicentric randomized study. Preliminary report. Int J Oncol 4:761–766.

    Google Scholar 

  152. Rosso R, Gardin G, Pronzato P, Camoriano A, Merlini L, Naso C, Rosso M, Barone C, Nascimben O, Ianniello G, Sturba F, Contu A, Baldini E, Giannessi PG, Conte PF (1993) The role of lonidamine in the treatment of breast cancer patients. Ann NY Acad Sci 698:349–356.

    PubMed  CAS  Google Scholar 

  153. Buccheri G, Ferrigno D (1994) A randomized trial of MACC chemotherapy with or without lonidamine in advanced non-small cell lung cancer. Eur J Cancer 30A:1424–1431.

    PubMed  CAS  Google Scholar 

  154. Orlandi L, Zaffaroni N, Gornati D, Veneroni S, Silvestrini R (1994) Potentiation of cisplatin cytotoxicity by lonidamine in primary culture of human ovarian cancer. Anticancer Res 14:1161–1164.

    PubMed  CAS  Google Scholar 

  155. Brandi M, Lorusso V, de Mi trio A, Fioretto A, Giannuzzi A, de Lena M (1994) Cisplatin (CDDP) plus lonidamine (LND) in advanced ovarian cancer pretreated with CDDP or carboplatin (CBDCA). Anticancer Res 5 (Suppl 1):65 (abstr).

    Google Scholar 

  156. Gadducci A, Brunetti I, Muttini M, Fanucchi A, Dargenio F, Giannessi P, Conte P (1994) Epidoxorubicin and lonidamine in refractory of recurrent epithelial ovarian cancer. Eur J Cancer 30A:1432–1435.

    PubMed  CAS  Google Scholar 

  157. Colella E, Merlano M, Blengio F, Angelini F, Ausili Cefaro GP, Scasso F, Lo Russo V, Cirulli S, Giannarelli D, Cognetti F (1994) Randomized phase II study of methotrexate (MTX) versus methotresxate plus lonidamine (MTX + LND) in recurrent and/or metastatic carcinoma of the head and neck. Eur J Cancer 30A:928–930.

    PubMed  CAS  Google Scholar 

  158. Magno L, Terraneo F, Bertoni F, Tordiglione M, Bardelli D, Rosignoli MT, Ciottoli GB (1994) Double-blind randomized study of lonidamine and radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 29:45–55.

    PubMed  CAS  Google Scholar 

  159. Privitera G, Ciottoli GB, Patane C, Palmucci T, Tafuri G, Marietta F, De Luca B, Magani F, De Gregorio M, Greco S (1987) Phase II double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung. Radiother Oncol 10:285–290.

    PubMed  CAS  Google Scholar 

  160. Scarantino CW, McCunniff AJ, Evans G, Young CW, Paggiarino DA (1994) a prospective randomized comparison of radiation therapy plus lonidamine versus radiation therapy plus placebo as initial treatment of clinically localized but nonresectable nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 29:999–1004.

    PubMed  Google Scholar 

  161. Stewart DJ, Eapen L, Girard A, Verma S, Genest P, Evans WK (1993) Phase II study of lonidamine plus radiotherapy in the treatment of brain metastases. J Neurooncol 15:19–22.

    PubMed  CAS  Google Scholar 

  162. Carapella CM, Paggi MG, Calvosa F, Cattani F, Floridi A, Jandolo B, Raus L, Riccio A (1991) The potential role of lonidamine in the combined treatment of malignant gliomas. A randomized stufy. Dev Oncol 66:205–207.

    Google Scholar 

  163. Newell DR, Mansi J, Hardy J, Button D, Jenns K, Smith IE, Picollo R, Cantanese B (1991) The pharmacokinetics of oral lonidamine in breast and lung cancer patients. Semin Oncol 18(suppl 4):11–17.

    PubMed  CAS  Google Scholar 

  164. Young CW, Currie VE, Kim JH, O’Hehir MA, Farag FM, Kinahan JE (1984) Phase I and clinical pharmacologic evaluation of lonidamine in patients with advanced cancer. Oncology 41 (suppl 1):60–65.

    PubMed  Google Scholar 

  165. Besner J-G, Leclaire R, Band PR, Deschamps M, De Sanctis AJ, Catanese B (1984) Pharmacokinetics of lonidamine after oral administration in cancer patients. Oncology 41 (Suppl 1):48–52.

    PubMed  Google Scholar 

  166. Gatzemeier U, Toomes H, Picollo R, Christoffel V, Lucker PW, Ulmer J (1991) Single- and multiple dose pharmacokinetics of lonidamine in patients suffering from non-small-cell lung cancer. Arzneim-Forsch 41:436–439.

    CAS  Google Scholar 

  167. Franchi F, Seminara P, Codacci Pisanelli G, Pagani Guazzugli Bonaiuti V, Giovagnorio F, Gualdi G (1994) Elevated doses of carmustine and mitomycin C, with lonidamine enhancement and autologous bone marrow transplantation in the treatment of advanced colorectal cancer: results from a pilot study. Eur J Cancer 30A:1420–1423.

    PubMed  CAS  Google Scholar 

  168. Hait WN, Aftab DT (1992) Rational design and pre-clinical pharmacology of drugs for reversing multidrug resistance. Biochem Pharmacol 43:103–107.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. John R. Murren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Germana Rappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yung-Chi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 679 Hoes Lane, Room 242, Piscataway, NJ, 08854, USA

    William N. Hait M.D., Ph.D.

  2. Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 679 Hoes Lane, Room 242, Piscataway, NJ, 08854, USA

    William N. Hait M.D., Ph.D.

  3. Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 679 Hoes Lane, Room 242, Piscataway, NJ, 08854, USA

    William N. Hait M.D., Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Kluwer Academic Publishers

About this chapter

Cite this chapter

Murren, J.R., Rappa, G., Cheng, YC. (1996). Multifunctional Modulators of Drug Resistance. In: Hait, W.N. (eds) Drug Resistance. Cancer Treatment and Research, vol 87. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-1267-3_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4613-1267-3_16

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-8540-3

  • Online ISBN: 978-1-4613-1267-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation