Cancer Chemotherapy and Pharmacology

, Volume 34, Supplement 1, pp S118–S126 | Cite as

Etoposide: current status and future perspectives in the management of malignant neoplasms

  • Chandra P. Belani
  • L. Austin Doyle
  • Joseph Aisner
Session 3: Clinical Trials and Applications Etoposide, Topoisomerase II, Malignant Neoplasms


Etoposide has demonstrated highly significant clinical activity against a wide variety of neoplasms, including germ-cell malignancies, small-cell lung cancer, non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, neuroblastoma, and soft-tissue sarcomas. It is also one of the important agents in the preparatory regimens given prior to bone marrow and peripheral stem-cell rescue. Despite its high degree of efficacy in a number of malignancies, the optimal dose, schedule, and dosing form remain to be defined. It is possible that continuous or prolonged inhibition of the substrate, i.e., topoisomerase II, may be the key factor for the cytotoxic effects of etoposide. Clinical studies have shown the activity of etoposide to be schedule-dependent, with prolonged dosing, best accomplished by the oral dosing form, offering a therapeutic advantage. This benefit awaits validation by prospective randomized studies, some of which are in progress. Recent clinical investigations have focused on the use of etoposide in combination with (a) cytokines to ameliorate myelosuppression, the dose-limiting toxicity of etoposide; (b) agents such as cyclosporin A and verapamil to alter the p-glycoprotein (mdr 1) function; and (c) topoisomerase I inhibitors to modulate the substrate upon which it acts. There is continued interest in the development of etoposide to its maximal clinical dimensions and in the examination of alternative biochemical and mechanistic approaches to further our understanding of this highly active agent.

Key words

Etoposide Topoisomerase II Malignant neoplasms 


  1. 1.
    O'Dwyer PJ, Leyland-Jones B, Alonso MT, et al (1985) Etoposide (VP-16-213): current status of an active anticancer drug. N Engl J Med 312:692–700Google Scholar
  2. 2.
    Williams SD, Birch R, Einhorn LH, et al (1987) Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435–1441Google Scholar
  3. 3.
    Clark P, Cottier B, Joel S, et al (1991) Two prolonged schedules of single agent oral etoposide of differing duration and dose in patients with untreated small cell lung cancer (SCLC) (abstract 931). Proc Am Soc Clin Oncol 10:268Google Scholar
  4. 4.
    Johnson DH, Hainsworth JD, Hande KR, et al (1991) Current status of etoposide in the management of small cell lung cancer. Cancer 67:231–233Google Scholar
  5. 5.
    Waits TM, Johnson DH, Hainsworth JD, et al (1992) Prolonged administration of oral etoposide in non-small cell lung cancer: a phase II trial. J Clin Oncol 10:292–296Google Scholar
  6. 6.
    Bender RA, Anderson T, Fisher RI, et al (1978) Activity of epipodophyllotoxin VP-16 in the treatment of combination chemotherapy-resistant non-Hodgkin's lymphoma. Am J Hematol 5: 203–209Google Scholar
  7. 7.
    Taylor RE, McElwain TJ, Barrett A, et al (1982) Etoposide as a single agent in relapsed advanced lymphoma. A phase II study. Cancer Chemother Pharmacol 7:175–177Google Scholar
  8. 8.
    Laubenstein LJ, Krigel RL, Odejnyk CM, et al (1984) Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 2:115–130Google Scholar
  9. 9.
    Horowitz ME (1989) Ewing's sarcoma: current status of diagnosis and treatment. Oncology 3:101–106Google Scholar
  10. 10.
    Carli M, Perilongo G, diMontezemolo LC, et al (1987) Phase II trial of cisplatin and etoposide in children with advanced soft tissue sarcoma: a report from the Italian Cooperative Rhabdomyosarcoma Group. Cancer Treat Rep 71:525–527Google Scholar
  11. 11.
    Kelsen DP, Magill G, Cheng E, et al (1982) Phase II trial of etoposide in the treatment of upper gastrointestinal malignancies (abstract). Proc Am Soc Clin Oncol 1:96Google Scholar
  12. 12.
    Kuhrie H, Meerpohl HG, Lenaz L, et al (1988) Etoposide in cisplatin-refractory ovarian cancer. Proc Am Soc Clin Oncol 7:A257Google Scholar
  13. 13.
    Slevin ML, Clark PI, Joel SP, et al (1989) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 7:1333–1340Google Scholar
  14. 14.
    Carney DN, Grogan L, Smit EF, et al (1990) Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 17 [Suppl 2]:49–53Google Scholar
  15. 15.
    Johnson DH, Greco FA, Strupp J, et al (1990) Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 8:1613–1617Google Scholar
  16. 16.
    Smyth RD, Pfeffer M, Scalzo A, et al (1985) Bioavailability and pharmacokinetics of etoposide (VP-16). Semin Oncol 12 [Suppl 2]: 48–51Google Scholar
  17. 17.
    Smit EF, Carney DN, Harford P, et al (1989) A phase II study of oral etoposide in elderly patients with small cell lung cancer. Thorax 44:631–633Google Scholar
  18. 18.
    Greco F (1991) Chronic oral etoposide. Cancer 67:303–309Google Scholar
  19. 19.
    Eagan RT, Carr DT, Fryak S, et al (1976) VP-16-213 versus polychemotherapy in patients with advanced small cell lung cancer. Cancer Treat Rep 60:949–951Google Scholar
  20. 20.
    Tucker RD, Ferguson A, Van Wyk C, et al (1978) Chemotherapy of small cell carcinoma of the lung with VP-16-213. Cancer 141:1710–1714Google Scholar
  21. 21.
    Matsui Y, Oshima S, Kado M, et al (1987) Phase II study of oral VP-16-213 in small cell lung cancer. Cancer 60:2882–2885Google Scholar
  22. 22.
    Hansen M, Hirsch F, Dombernowsky P, et al (1977) Treatment of small cell anaplastic carcinoma of the lung with oral solution of VP-16-213 (NSC 141540, 4′-demethylepipodophyllotoxin 9-4-(4,6-O-ethylidene-β-d-glycopryanoside). Cancer 40:633–637Google Scholar
  23. 23.
    Cavilli F, Sonntag RW, Jungi F, et al (1978) VP-16-213 monotherapy for remission induction of small cell lung cancer: a randomized trial using three dosage schedules. Cancer Treat Rep 62:473–475Google Scholar
  24. 24.
    Greco FA, Garrow GC, Johnson DH, et al (1992) Prolonged continuous infusion of low-dose etoposide in responsive neoplasm: preliminary phase I/II results. Proc Am Soc Clin Oncol 11:115Google Scholar
  25. 25.
    Einhorn LH, Greco A, Wampler G, et al (1987) Cytoxan, adriamycin, etoposide versus cytoxan, adriamycin and vincristine in the treatment of small cell lung cancer. Proc Am Soc Clin Oncol 6:168Google Scholar
  26. 26.
    Evans WK, Feld R, Murray N, et al (1987) Superiority of alternating non-cross resistant chemotherapy in extensive small cell lung cancer. Ann Intern Med 107:451–458Google Scholar
  27. 27.
    Natalir RB, Shank B, Hilaris BS, et al (1985) Combination cyclophosphamide, Adriamycin and vincristine rapidly alternating with combination cisplatin and VP-16 in treatment of small cell lung cancer. Am J Med 79:303–308Google Scholar
  28. 28.
    Woods RL, Levi JA (1984) Chemotherapy for small cell lung cancer (SCLC2w): a randomized study of maintenance therapy with cyclophosphamide, Adriamycin and vincristine (CAV) after remission induction therapy with cisplatinum (CIS-DDP), VP-16-213 and radiotherapy. Proc Am Soc Clin Oncol 3:214Google Scholar
  29. 29.
    Aisner J, Whitacre MY, Abrams J, et al (1986) Adriamycin, cytoxan, etoposide (ACE) and platinum, adriamycin, cytoxan, etoposide (PACE) for small cell carcinoma of the lung. Semin Oncol 13:54–62 (suppl 3)Google Scholar
  30. 30.
    Aisner J, Whitacre MY, Budman DR, et al (1992) Cisplatin, doxorubicin, cyclosphosphamide and etoposide combination chemotherapy for small-cell lung cancer. Cancer Chemother Pharmacol 29:435–438Google Scholar
  31. 31.
    Ruckdeschel JC (1991) Etoposide in the management of non-small cell lung cancer. Cancer 67:250–253Google Scholar
  32. 32.
    Niederle N, Ostermann J, Achterrath W, et al (1991) Etoposide in patients with previously untreated non-small cell lung cancer: a phase I study. Cancer Chemother Pharmacol 28:59–62Google Scholar
  33. 33.
    Rosso R, Salvati F, Ardizzoni A, et al (1991) Etoposide versus etoposide plus high-dose cisplatin in the management of advanced non-small cell lung cancer. Results of a prospective randomized FONICAP trial. Italian Lung Cancer Task Force. Cancer 66:130–134Google Scholar
  34. 34.
    Saxman S, Logie K, Stephens D, et al (1990) Phase II trial of daily oral etoposide in patients with surgically unresectable non-small cell lung cancer (abstract). Proc Am Soc Clin Oncol 9:238Google Scholar
  35. 35.
    Gatzcincier U, Neuhauss R, Heckmayr M (1991) Single agent oral etoposide in advanced NSCLC (chronic daily) and in elderly patients with SCLC (abstract) Lung Cancer 7 [Suppl]: 102Google Scholar
  36. 36.
    Miller AA, Tolley EA, Niell HB, Griffin JP, Mauer AM (1993) Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer. J Clin Oncol 11:1179–1188Google Scholar
  37. 37.
    Grunberg SM, Crowley JJ, Livingston R, et al (1993) Treatment of stage IV non-small cell lung cancer (NSCLC) with long term administration of oral otoposide (E) and oral cyclophosphamide (C). A Southwest Oncology Group study. J Clin Oncol 11: 1598–1601Google Scholar
  38. 38.
    Walls J, Devore R, Hainsworth JD, et al (1991) Carboplatin (CBDCA) plus prolonged administration of oral etoposide (E) in the treatment of non-small cell lung cancer (NSCLC): a phase I/II trial (abstract). Proc Am Soc Clin Oncol 10:257Google Scholar
  39. 39.
    Newlands E, Bagshawe K (1977) Epipodophyllotoxin derivative (VP16-213) in malignant teratomas and choriocarcinomas (letter). Lancet II:87Google Scholar
  40. 40.
    Hainsworth JD, Greco FA, Williams SD, et al (1984) VP-16-213 in the treatment of refractory germinal neoplasms. In: Issel BF, Muggia FM, Carter SK (eds) Etoposide (VP-16). Current status and new developments, Academic Press (Harcourt Brace Iovanovich, Publishers) London, pp 233–243Google Scholar
  41. 41.
    Williams S, Einhorn L, Greco F, et al (1980) VP-16-213 salvage therapy for refractory germinals neoplasms. Cancer 46:2154–2158Google Scholar
  42. 42.
    Birch R, Williams S, Cone A, et al (1986) Prognostic factors for favorable outcome in disseminated germ cell tumors. J Clin Oncol 4:400–407Google Scholar
  43. 43.
    Einhorn LH, Williams SD, Loehrer PJ, et al (1989) Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors. A Southwestern Cancer Study Group protocol. J Clin Oncol 7:387–391Google Scholar
  44. 44.
    Loehrer PJ, Elson P, Johnson DH, et al (1991) A randomized trial of cisplatin plus etoposide with or without bleomycin in favorable prognosis disseminated germ cell tumors (abstract) Proc Am Soc Clin Oncol 10:169Google Scholar
  45. 45.
    Nichols C, Williams S, Loehrer P, et al (1991) Randomized study of cisplatin dose intensity in advanced germ cell tumors: a Southwestern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:1163–1172Google Scholar
  46. 46.
    Wheeler B, Loehrer P, Wiliams S, et al (1986) Ifosfamide in refractory male germ cell tumors. J Clin Oncol 4:28–34Google Scholar
  47. 47.
    Loehrer PJ, Lauer R, Roth BJ, et al (1988) Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109:540–546Google Scholar
  48. 48.
    Stoter G, Sleijfer DT, Schornagel JH, et al (1993) BEP versus VIP in intermediate risk patients with disseminated non-seminomatous testicular cancer (NSTC). Proc Am Soc Clin Oncol 12:232Google Scholar
  49. 49.
    Nichols CR, Tricot G, Williams SD, et al (1989) Dose-intensive chemotherapy in refractory germ cell cancer — a phase I/II trial of high dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7:932–939Google Scholar
  50. 50.
    Rosti G, Salvioni R, Pizzocaro G, et al (1990) High dose chemotherapy (HDC) with carboplatin (CBP) and VP-16 in germ cell tumors: the Italian experience. In: Dicke K, Armitage JO, Dicke-Evinger MJ (eds) Proceedings of the Fifth International Bone Marrow Transplant Symposium, Omaha, Nebraska, pp 186Google Scholar
  51. 51.
    Bishop JF (1992) Etoposide in the treatment of acute leukemias. Semin Oncol 19 [Suppl 13]:33–38Google Scholar
  52. 52.
    Look AT, Dahl GV, Kalwinsky D, et al (1981) Effective remission induction of refractory childhood acute non-lymphocytic leukemia by VP-16-213 plus azacytidine. Cancer Treat Rep 65:995–999Google Scholar
  53. 53.
    Kalwinsky DK, Dahl GV, Mirro J, et al (1986) Induction failures in childhood acute nonlymphocytic leukemia: etoposide/5-azacytidine for cases refractory to daunorubicin/cytarabine. Med Pediatr Oncol 14:245–250Google Scholar
  54. 54.
    Letendre L, Hinemann V, Hoagland C, et al (1985) Phase I study of VP-16 (etoposide) and amsacrine (AMSA) in the treatment of refractory acute leukemia. Med Pediatr Oncol 13:232–234Google Scholar
  55. 55.
    Tschopp L, Fliedner VE von, Saufer C, et al (1986) Efficacy and clinical cross-resistances of a new combination therapy (AMSA/ VP16) in previously treated patients with acute non-lymphocytic leukemia. J Clin Oncol 4:318–324Google Scholar
  56. 56.
    Carella AM, Santini G, Giordano D, et al (1985) Idarubicin alone or in combination with cytarabine and etoposide (3+3+5 protocol) in acute non-lymphoblastic leukemia (letter) Leuk Res 9:631Google Scholar
  57. 57.
    Ho AD, Lipp T, Ehiger G, et al (1988) Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia — an active well tolerated regimen. J Clin Oncol 6:213–217Google Scholar
  58. 58.
    Lazzarino M, Morra E, Alessandrino EP, et al (1989) Treatment of relapsed or refractory acute myeloid leukemia in adults. Bone Marrow Transplant [Suppl] 4:121–123Google Scholar
  59. 59.
    Bishop JF, Joshua DE, Lowenthal RM, et al (1986) A phase I-II study of cytosine arabinoside, daunorubicin and VP16-213 in adult patients with acute non-lymphocytic leukemia. Aust NZ J Med 16:48–51Google Scholar
  60. 60.
    DeVita VT, Serpick AA, Carbone PP (1970) Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73:891–895Google Scholar
  61. 61.
    Glick J, Tsiatis A, Schilsky R, et al (1991) A randomized phase III trial of MOPP/ABVD hybrid vs. sequential MOPP-ABVD in advanced Hodgkin's disease: preliminary results of the Intergroup Trial (abstract). Proc Am Soc Clin Oncol 10:A941Google Scholar
  62. 62.
    Bonadonna G, Zucali R, Monfardini S, et al (1975) Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine and imidazole carboximide versus MOPP. Cancer 36:252–259Google Scholar
  63. 63.
    Longo DL, Young RC, Wesley M, et al (1986) Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol 4:1295–1306Google Scholar
  64. 64.
    Fox KA, Lippman SM, Cassady JR, et al (1987) Radiation therapy salvage of Hodgkin's, disease following chemotherapy. J Clin Oncol 5:544–549Google Scholar
  65. 65.
    Richards MA, Waxman JH, Ganesan TS, et al (1986) EVA treatment for recurrent or unresponsive Hodgkin's disease. Cancer Chemother Pharmacol 18: 51–53Google Scholar
  66. 66.
    Longo DL, Duffey PL, Young RC, et al (1992) Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol 10: 210–218Google Scholar
  67. 67.
    Tseng A Jr, Jacobs C, Coleman CN, et al (1987) Third line chemotherapy for resistant Hodgkin's disease with lomustine, etoposide and methotrexate. Cancer Treat Rep 71: 475–478Google Scholar
  68. 68.
    Pfreundschuh MG, Schoppe WD, Fuchss R, et al (1987) Lomustine, etoposide, vindesine and dexamethasone (CEVD) in Hodgkin's lymphoma refractory to cyclophosphamide, vincristine and decarbazine: a multicenter trial of the German Hodgkin's Study Group. Cancer Treat Rep 71: 1203–1207Google Scholar
  69. 69.
    Santoro A, Viviani SS, Valagussa P, et al (1986) CCNU, etoposide and prednimustine (CEP) in refractory Hodgkin's disease. Semin Oncol 13: 23–26Google Scholar
  70. 70.
    Cervantes F, Reverter JC, Montserrat E, et al (1986) Treatment of advanced resistant Hodgkin's disease with lomustine, etoposide and prednimustine. Cancer Treat Rep 70: 665–667Google Scholar
  71. 71.
    Hagemeister FBN, Tannir N, McLaughlin P, et al (1987) MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin's disease. J Clin Oncol 5: 556–561Google Scholar
  72. 72.
    Gribben JG, Linch DC, Singer CRJ, et al (1989) Successful treatment of refractory Hodgkin's disease by high dose combination chemotherapy and autologous bone marrow transplantation. Blood 73: 340Google Scholar
  73. 73.
    Yahalom J, Girlati S, Shank B, et al (1989) Total lymphoid irradiation, high dose chemotherapy and autologous bone marrow transplantation for chemotherapy-resistant Hodgkin's disease. Int J Radiat Oncol Biol Phys 17: 915Google Scholar
  74. 74.
    Fisher RI, Devita VT Jr, Hubbard SM, et al (1983) Diffuse aggressive lymphomas: increased survival after alternating flexible sequences of Pro MACE and MOPP chemotherapy. Ann Intern Med 98: 304–309Google Scholar
  75. 75.
    Longo DL, DeVita VT Jr, Duffy PL, et al (1991) Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol 9: 25–38Google Scholar
  76. 76.
    Frederico M, Moretti G, Gobbi PG, et al (1991) ProMACE-CytaBOM vs. MACOP-B in intermediate and high-grade NHL. Preliminary results of a prospective randomized trial. Leukemia 5: 95–101Google Scholar
  77. 77.
    O'Reilly SE, Hoskins P, Kleins P, et al (1991) MACP-B and VACOP-B in diffuse large cell lymphomas and MOPP/ABD in Hodgkin's disease. Ann Oncol 2: 17–23Google Scholar
  78. 78.
    Fisher RI, Gaynor E, Dahlberg S, et al (1993) Comparison of a standard regimen (CHOPE) with three intensive chemotherapy programmes for advanced non-Hodgkin's lymphoma. N Engl J Med 328: 1002–1006Google Scholar
  79. 79.
    Herzig RH (1991) High-dose etoposide and marrow transplantation. Cancer 67: 292–298Google Scholar
  80. 80.
    Spitzer GR, Cottler-Fox M, Torrisi J, et al (1989) Escalating doses of etoposide with a cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Bone Marrow Transplant 4: 559–565Google Scholar
  81. 81.
    Horning SJ, Chao NJ, Negrin RS, et al (1991) The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: preliminary data. Ann Oncol 2 [Suppl 1] 47–50Google Scholar
  82. 82.
    Freedman AS, Takvorian T, Anderson KC, et al (1990) Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment related mortality in 100 patients in sensitive relapse. J Clin Oncol 8: 784–791Google Scholar
  83. 83.
    Wilson WH, Bryant G, Bates S, et al (1991) Infusional etoposide (E), vincristine (O) and Adriamycin (H) with cyclophosphamide (C), prednisone (P) (EPOCH) and r-verapamil (RV) in relapsed lymphoma (abstract). Proc Am Soc Clin Oncol 10: 276Google Scholar
  84. 84.
    Beral V, Peterman TA, Berkelman RL, et al (1990) Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 335: 123Google Scholar
  85. 85.
    Shields P, Dawkins F, Holmlund J, et al (1989) Weekly low-dose multidrug chemotherapy (MDCT) plus pneumocystis prophylaxis for HIV-related Kaposi's sarcoma. Proc Am Soc Clin Oncol 8: 1Google Scholar
  86. 86.
    Preusser P, Wilke H, Achterrath W, et al (1989) Phase II study with the combination of etoposide, doxorubicin and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7: 1310–1317Google Scholar
  87. 87.
    Lerner A, Steele GD, Mayer RJ (1990) Etoposide, doxorubicin, cisplatin (EAP) chemotherapy for advanced gastric adenocarcinoma: results of a phase II trial (abstract). Proc Am Soc Clin Oncol 9: 103Google Scholar
  88. 88.
    Wilke H, Preusser P, Fink U, et al (1989) Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: a phase II study with etoposide, doxorubicin and cisplatin. J Clin Oncol 7: 1318–1326Google Scholar
  89. 89.
    Kelsen D, Atiq O, Saltz L, et al (1992) FAMTX versus etoposide, doxorubicin, and cisplatin: A random assignment trial in gastric cancer. J Clin Oncol 10: 541–548Google Scholar
  90. 90.
    Wilke H, Preusser P, Fink U, et al (1990) High dose folinic acid/etoposide/5-fluorouracil in advanced gastric cancer: a phase II study in elderly patients or patients with cardiac risk. Invest New Drugs 8: 65–70Google Scholar
  91. 91.
    Pastan I, Gottesman MM (1987) Multi-drug resistance in human cancer. N Engl J Med 316: 1388–1393Google Scholar
  92. 92.
    Goldstein LJ, Galski H, Fojo A, et al (1989) Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81: 116–124Google Scholar
  93. 93.
    Fojo A, Ueda K, Salmon DJ, et al (1987) Expression of a multidrug-resistant gene in human tumors and tissues. Proc Natl Acad Sci USA 84: 265–269Google Scholar
  94. 94.
    Nooter K, Herweijer H (1991) Multidrug resistance (mdr) genes in human cancer. Br J Cancer 63: 663–669Google Scholar
  95. 95.
    Slater L, Sweet P, Stupecky M, et al (1986) Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in-vitro. J Clin Invest 77: 1405–1408Google Scholar
  96. 96.
    Willingham M, Cornwell M, Cardarelli, C et al (1986) Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and sensitive KB cells: effects of verapamil and other drugs. Cancer Res 46: 591–594Google Scholar
  97. 97.
    Cornwell M, Pastan I, Gottesman M (1987) Certain calcium channel blockers bind specifically to multidrug resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem 26: 2166–2170Google Scholar
  98. 98.
    Lum BL, Kaubisch S, Yahanda AM, et al (1992) Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 10: 1635–1642Google Scholar
  99. 99.
    Yahanda M, Adler KM, Fisher GA, et al (1992) Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 10: 1624–1634Google Scholar
  100. 100.
    Eckhardt JR, Burris HA, Rodriquez GA, Fields SM, et al (1993) A phase I study of topoisomerase I and II inhibitors topotecan (T) and etoposide (E) (abstract). Proc Am Soc Clin Oncol 12: 137Google Scholar
  101. 101.
    Doyle LA, Hamburger AW, Goldstein LH, et al (1990) Interaction of recombinant human tumor necrosis factor (TNF) and etoposide in human lung cancer cell lines. Mol Biother 2: 169–174Google Scholar
  102. 102.
    Doyle LA, Guangiulio D, Hussain A, et al (1989) Differentiation of human variant small cell lung cancer cell lines to a classic morphology by retinoic acid. Cancer Res 49: 6745–6751Google Scholar
  103. 103.
    Von Hoff DD, McGill J, Davidson K, et al (1992) Preclinical leads for innovative uses of etoposide. Semin Oncol 19 [Suppl 13]: 10–13Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Chandra P. Belani
    • 1
  • L. Austin Doyle
    • 2
  • Joseph Aisner
    • 2
  1. 1.Pittsburgh Cancer Institute, Division of Medical OncologyUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.University of Maryland Cancer CenterBaltimoreUSA

Personalised recommendations