Skip to main content
SpringerLink
Log in

New Oral Chemotherapeutic Agents for Lung Cancer

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Anticancer treatment has recently shifted to include a broad range of antineo-plastic therapies. Old agents are continuously being re-evaluated, and new mechanisms of treatment are rapidly being explored and developed. At the same time, the patient’s perceived quality of life, adverse effects of therapy, time demands, and healthcare costs have become paramount in the treatment process. Lung cancer is the most common cause of cancer death in the USA, and because many of the patients are older or debilitated, these issues become all the more important. The oral administration of anticancer therapy offers both quality-of-life and healthcare cost advantages. Oral forms of 3 new cytotoxic agents and 2 novel oral therapies are discussed. Vinorelbine, a vinca alkaloid, has well documented activity in non-small cell lung cancer. Myelosuppression is dose limiting; neuro-toxicity is rare. Satraplatin (JM-216), an oral platinum derivative, shows activity in lung cancer with a favourable adverse effect profile, with no neurotoxicity or nephrotoxicity The oral topoisomerase I inhibitor topotecan may be ideal for obtaining long term low plasma drug concentrations, which appears to maximise efficacy. LGD-1069 is a retinoid X receptor agonist that modulates cell proliferation, and BAY-129566, a matrix metalloproteinase inhibitor, appears to interrupt both the processes of angiogenesis and metastasis. LGD-1069 and BAY-129566 are nontraditional anticancer agents which may be used in conjunction with chemotherapy, other modalities, or in prevention. These 5 agents will be discussed with particular reference to recent developments in the treatment of lung cancer.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Parker SL, Tong T, Bolden S, et al. Cancer statistics 1997. CA Cancer J Clin 1997; 47: 5–27

    Article  PubMed  CAS  Google Scholar 

  2. Anonymous. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311: 899–909

  3. Cullen MH, Woodroffe CM, Billingham LJ, et al. Mitomycin, ifosfamide and cisplatin in non-small cell lung cancer: 2. Results of a randomised trial in patients with extensive disease. Lung Cancer 1997; 18 Suppl. 1: 5

    Google Scholar 

  4. Coates A, Dillenbeck CF, McNeil DR, et al. On the receiving end—II. Linear analogue self-assessment (LASA) in evaluation of aspects of the quality of life of cancer patients receiving therapy. Eur J Cancer Clin Oncol 1983; 19: 1633–7

    Article  PubMed  CAS  Google Scholar 

  5. Coates A, Abraham S, Kaye SB, et al. On the receiving end—patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983; 19: 203–8

    Article  PubMed  CAS  Google Scholar 

  6. Fellous A, Ohayon R, Vacassin T, et al. Biochemical effects of Navelbine® on tubulin and associated proteins. Semin Oncol 1989; 16 Suppl. 4: 9–14

    PubMed  CAS  Google Scholar 

  7. Potier P. The synthesis of Navelbine® —prototype of a new series of vinblastine derivatives. Semin Oncol 1989; 16 Suppl. 4: 2–4

    PubMed  CAS  Google Scholar 

  8. Binet S, Fellous A, Lataste H, et al. In situ analysis of the action of Navelbine on various types of microtubules using immunofluorescence. Semin Oncol 1989; 16 Suppl. 4: 5–8

    PubMed  CAS  Google Scholar 

  9. Binet S, Chaineau E, Fellous A, et al. Immunofluorescence study of the action of navelbine, vincristine and vinblastine on mitotic and axonal microtubules. Int J Cancer 1990; 46: 262–6

    Article  PubMed  CAS  Google Scholar 

  10. Krikorian A, Rahmani R, Bromet M, et al. Pharmacokinetics and metabolism of Navelbine®. Semin Oncol 1989; 16 Suppl. 4: 21–5

    PubMed  CAS  Google Scholar 

  11. Nelson R, Dyke RW, Root MA. Comparative pharmacokinetics of vindesine, vincristine, and vinblastine in patients with cancer. Cancer Treat Rev 1980; 7 Suppl. 1: 17–24

    Article  PubMed  Google Scholar 

  12. Nelson R. The comparative clinical pharmacology and pharmacokinetics of vindesine, vincristine, and vinblastine in human patients with cancer. Med Pediatr Oncol 1982; 10: 115–27

    Article  PubMed  CAS  Google Scholar 

  13. Leveque D, Quoix E, Dumont P, et al. Pulmonary distribution of vinorelbine in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 1993; 33: 176–8

    Article  PubMed  CAS  Google Scholar 

  14. Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12: 360–7

    PubMed  Google Scholar 

  15. Hodes M, Rohn R, Bond W. Vincaleukoblastine III. Clinical trial with the oral preparation. Cancer Chemother Rep 1961; 14: 129–38

    CAS  Google Scholar 

  16. Korst DR, Nixon JC. Oral administration of vinblastine sulfate (NSC-49842) to cancer patients. Cancer Chemother Rep 1965; 45: 53–6

    PubMed  CAS  Google Scholar 

  17. MacDonald Jr CA, Lacher MJ. Oral vinblastine sulfate in Hodgkin’s disease. Clin Pharmacol Ther 1966; 7: 534–41

    PubMed  Google Scholar 

  18. Wilson HE, Louis J. The response of Hodgkin’s disease to treatment with oral vinblastine sulfate. Ann Intern Med 1967; 67: 303–8

    PubMed  CAS  Google Scholar 

  19. Leveque D, Jehl F. Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet 1996; 31: 184–97

    Article  PubMed  CAS  Google Scholar 

  20. Zhou XJ, Bore P, Monjanel S, et al. Pharmacokinetics of Navelbine after oral administration in cancer patients. Cancer Chemother Pharmacol 1991; 29: 66–70

    Article  PubMed  CAS  Google Scholar 

  21. Rowinsky EK, Noe DA, Trump DL, et al. Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors. J Clin Oncol 1994; 12: 1754–63

    PubMed  CAS  Google Scholar 

  22. Bore P, Rahmani R, Van Cantfort J, et al. Pharmacokinetics of a new anticancer drug, navelbine, in patients. Cancer Chemother Pharmacol 1989; 23: 247–51

    Article  PubMed  CAS  Google Scholar 

  23. Jehl F, Quoix E, Leveque D, et al. Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography. Cancer Res 1991; 51: 2073–6

    PubMed  CAS  Google Scholar 

  24. Wargin WA, Lucas VS. The clinical pharmacokinetics of vinorelbine (navelbine). Semin Oncol 1994; 21 Suppl. 10: 21–7

    PubMed  CAS  Google Scholar 

  25. Favre R, Delgado M, Besenval M. Phase I trial of escalating doses of orally administered Navelbine. Pt II. Clinical results. Proc Am Soc Clin Oncol 1989; 8: 64A

    Google Scholar 

  26. Rahmani R, Bore P, Cano JP. Phase I trial of escalating doses of orally administered Navelbine. Pt I. Pharmacokinetics. Proc Am Soc Clin Oncol 1989; 8: 74A

    Google Scholar 

  27. Rahmani R, Zhou XJ, Bore P. Oral administration of [3H]Navelbine in patients: comparative pharmacokinetics using radioactive and radioimmunologic determination methods. Anticancer Drugs 1991; 2: 405–10

    Article  PubMed  CAS  Google Scholar 

  28. Lucas S, Donehower R, Rowinsky E. Clinical results of a study of the absolute bioavailability and pharmacokinetics of weekly vinorelbine liquid-filled soft gelatin capsules at full therapeutic doses in patients with solid tumors. Proc Am Soc Clin Oncol 1992; 11: 287A

    Google Scholar 

  29. Zhou XJ, Zhou-Pan XR, Favre R, et al. Relative bioavailability of two oral formulations of navelbine in cancer patients. Biopharm Drug Dispos 1994; 15: 577–86

    Article  PubMed  CAS  Google Scholar 

  30. Vokes EE, Rosenberg RK, Jahanzeb M, et al. Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer. J Clin Oncol 1995; 13: 637–44

    PubMed  CAS  Google Scholar 

  31. Depierre A, Lemarie E, Dabouis G, et al. A Phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol 1991; 14: 115–9

    Article  PubMed  CAS  Google Scholar 

  32. Crawford J, O’Rourke M, Schiller JH, et al. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol 1996; 14: 2774–84

    PubMed  CAS  Google Scholar 

  33. Spicer D, McCaskill-Stevens W, Oken M, et al. Oral Navelbine in women with previously treated advanced breast cancer: a US multicenter Phase II trial. Proc Am Soc Clin Oncol 1994; 13: 76A

    Google Scholar 

  34. Lucas S, Rowinsky E, Wargin W. Results of a study of the effect of food on the bioavailability and pharmacokinetics of Navelbine® liquid-filled soft gelatin capsules. Proc Am Soc Clin Oncol 1993; 12: 160A

    Google Scholar 

  35. Rowinsky EK, Lucas VS, Hsieh AL, et al. The effects of food and divided dosing on the bioavailability of oral vinorelbine. Cancer Chemother Pharmacol 1996; 39: 9–16

    Article  PubMed  CAS  Google Scholar 

  36. Winer EP, Chu L, Spicer DV. Oral vinorelbine (navelbine) in the treatment of advanced breast cancer. Semin Oncol 1995; 22 Suppl. 5: 72–8

    PubMed  CAS  Google Scholar 

  37. Robieux I, Sorio R, Vitali V, et al. Pharmacokinetics of vinorelbine in breast cancer patients with liver metastases. Proc Am Soc Clin Oncol 1995; 14: 458A

    Google Scholar 

  38. Rosenberg B, Van Camp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 1965; 205: 698–9

    Article  PubMed  CAS  Google Scholar 

  39. Rosenberg B, Van Camp L, Grimley EB, et al. The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum (IV) complexes. J Biol Chem 1967; 242: 1347–52

    PubMed  CAS  Google Scholar 

  40. Rosenberg B, Van Camp L, Trosko JE, et al. Platinum compounds: a new class of potent antitumor agents. Nature 1969; 222: 385–6

    Article  PubMed  CAS  Google Scholar 

  41. Higby DJ, Wallace HJ, Albert DJ, et al. Diamminedichloroplatinum: a Phase I study showing responses in testicular and other tumors. Cancer 1974; 33: 1219–25

    Article  PubMed  CAS  Google Scholar 

  42. Harrap KR, Jones M, Wilkinson CR, et al. Antitumor, toxic and biochemical properties of cisplatin and eight other platinum complexes. In: Prestayko AW, editor. Cisplatin: current status and new developments. New York: Academic Press, 1980: 193–212

    Google Scholar 

  43. Shea TC, Flaherty M, Elias A, et al. A Phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 1989; 7: 651–61

    PubMed  CAS  Google Scholar 

  44. Harrap KR, Kelland LR, Jones M, et al. Platinum coordination complexes which circumvent cisplatin resistance. Adv Enzyme Regul 1991; 31: 31–43

    Article  PubMed  CAS  Google Scholar 

  45. Harrap KR, Murrer BA, Giandomenico C, et al. A novel class of orally active platinum IV coordination complexes which circumvent cisplatin resistance in vitro. Proc Am Assoc Cancer Res 1991;32: 428A

    Google Scholar 

  46. Harrap KR, Morgan SE, Murrer BA, et al. New platinum drugs capable of oral administration. Ann Oncol 1992; 3 Suppl. 1: 116A

    Google Scholar 

  47. Giandomenico CM, Abrams MJ, Murrer BA, et al. Synthesis and reactions of a new class of orally active Pt(IV) antitumor complexes. In: Howell SB, editor. Platinum and other metal coordination compounds in cancer chemotherapy. New York: Plenum Publishing Corp., 1991: 93–100

    Google Scholar 

  48. Kelland LR, Murrer BA, Abel G, et al. Structure-activity relationships in a series of novel platinum (II) and platinum (IV) ammine/amine complexes evaluated against a panel of human ovarian carcinoma cell lines. J Cell Pharmacol 1991; 2: 331–42

    Google Scholar 

  49. Twentyman PR, Wright KA, Mistry P, et al. Sensitivity to novel platinum compounds of panels of human lung cancer cell lines with acquired and inherent resistance to cisplatin. Cancer Res 1992; 52: 5674–80

    PubMed  CAS  Google Scholar 

  50. Kelland LR, Mellish KJ, Abel G, et al. Circumvention of transport-mediated acquired cisplatin resistance in human cancer cell lines by the orally active platinum drug, Bis-acetatoammine dichloro(cyclohexylamine) platinum (IV) (JM216). Proc Am Assoc Cancer Res 1993; 34: 400A

    Google Scholar 

  51. Mellish KJ, Kelland LR, Harrap KR. In vitro platinum drug chemosensitivity of human cervical squamous cell carcinoma cell lines with intrinsic and acquired resistance to cisplatin. Br J Cancer 1993; 63: 240–50

    Article  Google Scholar 

  52. Rose WC, Crosswell AR, Schurig JE, et al. Preclinical antitumor activity of orally administered platinum (IV) complexes. Cancer Chemother Pharmacol 1993; 32: 197–203

    Article  PubMed  CAS  Google Scholar 

  53. Harrap KR. Initiatives with platinum-and quinazoline-based antitumor molecules —Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer Res 1995; 55: 2761–8

    CAS  Google Scholar 

  54. Casazza AM, Rose WC, Comereski C, et al. JM 216: a novel orally active platinum complex. Proc Am Assoc Cancer Res 1992; 33: 536A

    Google Scholar 

  55. Kelland LR, Mistry P, Abel G, et al. Mechanism-related circumvention of acquired cis-diamminedichloroplatinum(II) resistance using two pairs of human ovarian carcinoma cell lines by ammine/amine platinum(IV) dicarboxylates. Cancer Res 1992; 52: 3857–64

    PubMed  CAS  Google Scholar 

  56. Kelland LR, Murrer BA, Abel G, et al. Ammine/amine platinum (IV) dicarboxylate complexes: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cells lines. Cancer Res 1992; 52: 822–8

    PubMed  CAS  Google Scholar 

  57. McKeage MJ, Kelland LR, Boxall FE, et al. Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo. Cancer Res 1994; 54: 4118–22

    PubMed  CAS  Google Scholar 

  58. McKeage MJ, Morgan SE, Boxall FE, et al. Preclinical toxicology and tissue platinum distribution of novel oral antitumor platinum complexes: ammine/amine platinum (IV) dicarboxylates. Cancer Chemother Pharmacol 1994; 33: 497–503

    Article  PubMed  CAS  Google Scholar 

  59. McKeage MJ, Morgan SE, Boxall FE, et al. Lack of nephrotoxicity of oral ammine/amine platinum(IV) dicarboxylate complexes in rodents. Br J Cancer 1993; 67: 996–1000

    Article  PubMed  CAS  Google Scholar 

  60. Raynaud FI, Boxall FE, Goddard P, et al. Metabolism, protein binding and in vivo activity of the oral platinum drug JM216 and its biotransformation products. Anticancer Res 1996; 16: 1857–62

    PubMed  CAS  Google Scholar 

  61. McKeage MJ, Mistry P, Ward J, et al. A Phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration. Cancer Chemother Pharmacol 1995; 36: 451–8

    Article  PubMed  CAS  Google Scholar 

  62. McKeage MJ, Raynaud F, Ward J, et al. Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 1997; 15: 2691–700

    PubMed  CAS  Google Scholar 

  63. Judson I, Cerny T, Epelbaum R, et al. Phase II trial of the oral platinum complex JM216 in non-small cell lung cancer: an EORTC early clinical studies group investigation. Ann Oncol 1997; 8: 604–6

    Article  PubMed  CAS  Google Scholar 

  64. Fokkema E, Lunenberg J, van Putten JWG, et al. Randomized Phase II study of oral JM216 versus intravenous cisplatin in non-small cell lung cancer: preliminary results. Proc Am Soc Clin Oncol 1998; 17: 483A

    Google Scholar 

  65. Groen HJM, Smit EF, Bauer J. A Phase II study of oral platinum JM-216 as first-line treatment in small cell lung cancer. Proc Am Soc Clin Oncol 1996; 15: 378A

    Google Scholar 

  66. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524–30

    Article  PubMed  CAS  Google Scholar 

  67. van de Vaart PJ, Klaren HM, Hofland I, et al. Oral platinum analogue JM216, a radiosensitizer in oxic murine cells. Int J Radiat Biol 1997; 72: 675–83

    Article  PubMed  Google Scholar 

  68. Hoffman P, Mauer A, Haraf D, et al. Oral JM-216 plus concomitant radiotherapy for patients with advanced malignancies of the chest. Proc Am Soc Clin Oncol 1998; 17: 488A

    Google Scholar 

  69. Gottlieb JA, Guarino AM, Call JB, et al. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC 100880). Cancer Chemother Rep 1970; 54: 461–70

    PubMed  CAS  Google Scholar 

  70. Muggia FM, Creaven PJ, Hansen HH, et al. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC 100880): correlation with preclinical studies. Cancer Chemother Rep 1972; 56: 515–21

    PubMed  CAS  Google Scholar 

  71. Verweij J. New promising anticancer agents in development: what comes next? Cancer Chemother Pharmacol 1996; 38 Suppl.: S3–S10

    Article  PubMed  CAS  Google Scholar 

  72. Creaven PJ, Allen LM, Muggia FM. Plasma camptothecin (NSC-100880) levels during a 5-day course of treatment: relation to dose and toxicity. Cancer Chemother Rep 1972; 56: 573–8

    PubMed  CAS  Google Scholar 

  73. Moertel CCG, Schutt AJ, Reitemeier RJ, et al. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rev 1972; 56: 95–101

    CAS  Google Scholar 

  74. Schmitt B, Buhre U, Vosberg HP. Characterisation of size variant of type I DNA topoisomerase isolated from calf thymus. Eur JBiochem 1984; 144: 127–34

    Article  CAS  Google Scholar 

  75. Juan C, Hwang J, Liu LF, et al. Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20ql2-13. 2. Proc NatlAcad Sci USA 1988; 85: 8910–3

    Article  CAS  Google Scholar 

  76. Horwitz SB, Horwitz MS. Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Res 1973; 33: 2834–6

    PubMed  CAS  Google Scholar 

  77. Hsiang YH, Hertzberg R, Hecht S, et al. Camptothecin induces protein-limited DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260: 14873–8

    PubMed  CAS  Google Scholar 

  78. Mattern MR, Mong SM, Bartus HF, et al. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Cancer Res 1987; 47: 1793–8

    PubMed  CAS  Google Scholar 

  79. Hsiang YH, Lihou MG, Liu LF. Arrest of replication forks by drug stabilized topoisomerase-I-DNAcleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989; 49: 5077–82

    PubMed  CAS  Google Scholar 

  80. Liu L. DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem 1989; 58: 351–74

    Article  PubMed  CAS  Google Scholar 

  81. Creemers GJ, Schellens JHM, Beijnen JH, et al. Bioavailability of oral topotecan, a new topoisomerase I inhibitor. Proc Am Soc Clin Oncol 1994; 13: 132A

    Google Scholar 

  82. Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors: topotecan and irinotecan. Cancer Treat Rev 1994; 20: 73–96

    Article  PubMed  CAS  Google Scholar 

  83. McCabe FL, Johnson RK. Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan. Cancer Invest 1994; 12: 308–13

    Article  PubMed  CAS  Google Scholar 

  84. Creemers GJ, Gerrits CJH, Eckardt JR, et al. Phase I and pharmacologie study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors. J Clin Oncol 1997; 15: 1087–93

    PubMed  CAS  Google Scholar 

  85. Giovanella BC, Stehlin JS, Wall ME, et al. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 1989; 246: 1046–8

    Article  PubMed  CAS  Google Scholar 

  86. Burris HA, Hanauske AR, Johnson RK, et al. Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst 1992; 84: 1816–20

    Article  PubMed  CAS  Google Scholar 

  87. Houghton PJ, Cheshire PJ, Myers L, et al. Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) against xenografts derived from adult and childhood tumors. Cancer Chemother Pharmacol 1992; 31: 229–39

    Article  PubMed  CAS  Google Scholar 

  88. Verweij J, Lund B, Beijnen JH, et al. Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor. Ann Oncol 1993; 4: 673–8

    PubMed  CAS  Google Scholar 

  89. Hochster H, Liebes L, Speyer J, et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 1994; 12: 553–9

    PubMed  CAS  Google Scholar 

  90. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48: 1722–6

    PubMed  CAS  Google Scholar 

  91. Ardizzoni A, Hansen HH, Dombernowsky P, et al. Phase II study of topotecan in refractory and sensitive small cell lung cancer. Eur J Cancer 1995; 31A Suppl. 5: S19

    Article  Google Scholar 

  92. Broom C. Clinical studies of topotecan. Ann NY Acad Sci 1996; 803: 264–71

    Article  PubMed  CAS  Google Scholar 

  93. Rowinsky EK, Grochow LB, Hendricks CB, et al. Phase I and pharmacologie study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647–56

    PubMed  CAS  Google Scholar 

  94. Wall JA, Burris HA, Von Hoff DD, et al. A Phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor, topotecan (SK & F 104864), given as an intravenous bolus every 21 days. Anticancer Drugs 1992; 3: 337–45

    Article  PubMed  CAS  Google Scholar 

  95. Schiller JH, Kim K, Johnson, D. Phase II study of topotecan in extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 1994; 13: 330A

    Google Scholar 

  96. Schiller J, Von Pawel J, Shepherd F, et al. Topotecan versus cyclophosphamide, doxorubicin and vincristine for the treatment of patients with recurrent small cell lung cancer: a Phase II study. Proc Am Soc Clin Oncol 1998; 17: 456A

    Google Scholar 

  97. Schellens JHM, Creemers GJ, Beijnen JH, et al. Bioavailability and pharmacokinetic s of oral topotecan: a new topoisomerase I inhibitor. Br J Cancer 1996; 73: 1268–71

    Article  PubMed  CAS  Google Scholar 

  98. Kuhn J, Rizzo J, Eckhardt J, et al. Phase I bioavailability study of oral topotecan. Proc Am Soc Clin Oncol 1995; 14: 474A

    Google Scholar 

  99. Kizaki M, Dawson MI, Heyman R, et al. Effects of novel retinoid X receptor-selective ligands on myeloid leukemic differentiation and proliferation in vitro. Blood 1996; 87: 1977–84

    PubMed  CAS  Google Scholar 

  100. Kizaki M, Nakajima H, Mori S, et al. Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells. Blood 1994; 83: 3289–97

    PubMed  CAS  Google Scholar 

  101. Miller VA, Benedetti FM, Rigas JR, et al. Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 1997; 15: 790–5

    PubMed  CAS  Google Scholar 

  102. Boehm MF, Zhang L, Badea BA, et al. Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 1994; 37: 2930–41

    Article  PubMed  CAS  Google Scholar 

  103. Boehm MF, Zhang L, Zhi L, et al. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem 1995; 38: 3146–55

    Article  PubMed  CAS  Google Scholar 

  104. Zhang XK, Hoffmann B, Tran PBV, et al. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature 1992; 355: 441–6

    Article  PubMed  CAS  Google Scholar 

  105. Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992; 358: 771–4

    Article  PubMed  CAS  Google Scholar 

  106. Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 1992; 17: 427–33

    Article  PubMed  CAS  Google Scholar 

  107. Nagy L, Thomazy VA, Shipley GL, et al. Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 1995; 15: 3540–51

    PubMed  CAS  Google Scholar 

  108. Kligman AM, Fulton JE, Plewig G. Topical vitamin A acid in acne vulgaris. Arch Dermatol 1969; 99: 469–76

    Article  PubMed  CAS  Google Scholar 

  109. Peck GL, Olsen TG, Yoder FW. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 1979; 300: 329–33

    Article  PubMed  CAS  Google Scholar 

  110. Baden HP, Buxman MM, Weinstein GD, et al. Treatment of ichthyosis with isotretinoin. J Am Acad Dermatol 1982; 6 Suppl. 2: 716–20

    Article  PubMed  CAS  Google Scholar 

  111. Peck GL, Olsen TG, Butkus D, et al. Isotretinoid versus placebo in the treatment of cystic acne. A randomized doublc-blind study. J Am Acad Dermatol 1982; 6: 735–45

    Article  PubMed  CAS  Google Scholar 

  112. Lippman SM, Parkinson DR, Itri LM, et al. 13-cis-Retinoic acid and interferon α-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 1992; 84: 235–41

    Article  PubMed  CAS  Google Scholar 

  113. Lippman SM, Kavanagh JJ, Paredes Espinoza M, et al. 13-cis-Retinoic acid plus interferon α-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 1992; 84: 241–5

    Article  PubMed  CAS  Google Scholar 

  114. Benner SE, Winn RJ, Lippman SM, et al. Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemotherapy study. JNatl Cancer Inst 1993; 85: 44–7

    Article  CAS  Google Scholar 

  115. Benner SE, Lippman SM, Hong WK. Retinoid chemoprevention of second primary tumors. Semin Hematol 1994; 31 Suppl. 5: 26–30

    PubMed  CAS  Google Scholar 

  116. Koeffler P. Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood 1983; 62: 709–21

    PubMed  CAS  Google Scholar 

  117. Douer D, Koeffler P. Retinoic acid. Inhibition of the clonal growth of human myeloid leukemia cells. J Clin Invest 1982; 69: 277–83

    Article  PubMed  CAS  Google Scholar 

  118. Lotan R, Lotan D, Sacks PG. Inhibition of tumor cell growth by retinoids. Methods Enzymol 1990; 190: 100–10

    Article  PubMed  CAS  Google Scholar 

  119. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–72

    PubMed  CAS  Google Scholar 

  120. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990; 76: 1704–9

    CAS  Google Scholar 

  121. Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic patients. Blood 1991; 78: 1413–9

    PubMed  CAS  Google Scholar 

  122. Miller Jr WH, Jakubowski A, Tong WP, et al. 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood 1995; 85: 3021–7

    PubMed  CAS  Google Scholar 

  123. Delia D, Aiello A, Lombardi L, et al. N-(4-hydroxy-phenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. Cancer Res 1993; 53: 6036–41

    PubMed  CAS  Google Scholar 

  124. Mehta K, McQueen T, Neamati N. Activation of retinoid receptors RAR-a and RXR-a induces differentiation and apoptosis, respectively, in HL-60 cells. Cell Growth Differ 1996; 7: 179–86

    PubMed  CAS  Google Scholar 

  125. Shirley MA, Wheelan P, Howell SR, et al. Oxidative metabolism of a retinoid and rapid phase II metabolite identification by mass spectrometry. Drug Metab Dispos 1997; 25: 1144–9

    PubMed  CAS  Google Scholar 

  126. Gottardis MM, Bischoff ED, Shirley MA, et al. Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand. Cancer Res 1996; 56: 5566–70

    PubMed  CAS  Google Scholar 

  127. Bischoff ED, Gottardis MM, Moon TE, et al. Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (Targretin) causes complete regression of mammary carcinoma. Cancer Res 1998; 58: 479–84

    PubMed  CAS  Google Scholar 

  128. Cawston TE, Galloway WA, Mercer E, et al. Purification of rabbit bone inhibitor of collagenase. Biochem J 1981; 195: 159–65

    PubMed  CAS  Google Scholar 

  129. Dean DD, Woessner Jr JF. Extracts of human articular cartilage contain an inhibitor of tissue metalloproteinases. Biochem J 1984; 218: 277–80

    PubMed  CAS  Google Scholar 

  130. Hasty KA, Reife RA, Kang AH, et al. The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis. Arthritis Rheum 1990; 33: 388–97

    Article  PubMed  CAS  Google Scholar 

  131. Brown PD. Matrix metalloproteinase inhibitors: a new class of anticancer agent. Curr Opin Invest Drugs 1993; 2: 617–26

    Google Scholar 

  132. Hibner B, Card A, Flynn C, et al. Bay 12-9566, a novel, biphenyl matrix metalloproteinase inhibitor, demonstrates anti-invasive and anti-angiogenic properties. Proc Am Assoc Cancer Res 1998; 39: 302A

    Google Scholar 

  133. Bull C, Flynn C, Eberwein D, et al. Activity of the biphenyl matrix metalloproteinase inhibitorBAY 12-9566 in murine in vivo models. Proc Am Assoc Cancer Res 1998; 39: 302A

    Google Scholar 

  134. Flynn C, Bull C, Eberwein D, et al. Anti-metastatic activity of BAY 12-9566 in a human colon carcinoma HCT116 or-thotopic model. Proc Am Assoc Cancer Res 1998; 39: 301A

    Google Scholar 

  135. Shah A, Sundaresan P, Humphrey R, et al. Comparative pharmacokinetics of BAY 12-9566, a metalloproteinase inhibitor, in healthy volunteers and cancer patients. Proc Am Assoc Cancer Res 1998; 39: 521A

    Google Scholar 

  136. Hirte H, Goel R, Major P, et al. Pharmacokinetics of BAY12-9566: early results of a Canadian Phase I dose escalation study in cancer patients. Proc Am Assoc Cancer Res 1998; 39: 364A

    Google Scholar 

  137. Langer CJ. The role of tegafur.uracil in pulmonary malignancy. Drugs 1999; 58 Suppl. 3: 71–5

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dartmouth Medical School, Hanover, New Hampshire, USA

    Elizabeth M. Bengtson &  James R. Rigas

  2. Section of Hematology/Oncology, Department of Medicine, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Norris Cotton Cancer Center, Lebanon, New Hampshire, 03756-0001, USA

    James R. Rigas

Authors
  1. Elizabeth M. Bengtson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James R. Rigas
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bengtson, E.M., Rigas, J.R. New Oral Chemotherapeutic Agents for Lung Cancer. Drugs 58 (Suppl 3), 57–69 (1999). https://doi.org/10.2165/00003495-199958003-00009

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199958003-00009

Keywords

Search

Navigation