Phase II trial of perillyl alcohol in patients with metastatic colorectal cancer

  • Sherry Morgan MeadowsEmail author
  • Daniel Mulkerin
  • Jordan Berlin
  • Howard Bailey
  • Jill Kolesar
  • Deb Warren
  • James P. Thomas
Research Article


Purpose. This is a phase II study of perillyl alcohol in the treatment of patients with metastatic colorectal carcinoma. The primary endpoint is time to progression. Secondary objectives are to evaluate objective response rate and toxicity.

Patients and Methods. Eligible patients had metastatic adenocarcinoma of the colon or rectum. Patients received perillyl alcohol orally at a dose of 1200 mg/m2. Dose escalation to 1,600mg/m2 was allowed.

Results. Twenty-seven patients were enrolled. The median time to progression was 1.8 months (range 1 to 3 mo). Four patients received less than one cycle and were not evaluable for response. Of the remaining 23, all had progressive disease. There were no complete or partial responses. Toxicity was relatively mild, with fatigue, nausea and anemia predominating. Three patients withdrew from therapy for toxicity (grade 3 belching, bloating; grade 2 nausea, fatigue, vomiting, anorexia and increase perspiration; grade 1 anorexia).

Discussion. Despite preclinical evidence of anticancer activity, oral perillyl alcohol administered at this dose and formulation does not appear to have clinical antitumor activity when used for patients with advanced colorectal carcinoma.

Key Words

Perillyl alcohol monoterpenes colon cancer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemel A, Thomas A, Murray T. Cancer Statistics 2002. CA Cancer J Clin 2000;52:23–47.CrossRefGoogle Scholar
  2. 2.
    Cunningham D, Pyrhnen S, James RD, et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413–1418.PubMedCrossRefGoogle Scholar
  3. 3.
    Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan plus fluorouracil by continuous infusion after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1407–1412.PubMedCrossRefGoogle Scholar
  4. 4.
    Douillard J-Y, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet 2000;355(9209):1041–1047.PubMedCrossRefGoogle Scholar
  5. 5.
    Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905–914.PubMedCrossRefGoogle Scholar
  6. 6.
    Maindraul-Goebel F, Louvet C, Andr T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FLOFOX6). European Journal of Cancer 1999;35(9):1338–1342.CrossRefGoogle Scholar
  7. 7.
    De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.PubMedGoogle Scholar
  8. 8.
    Gauccgettu S, Perpoint B, Zidani R, et al. Phase III multi-center randomized trial of oxaliplatin added to chronomo ulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136–147.Google Scholar
  9. 9.
    Crowell PL and Gould MN. Chemoprevention of mammary cancer by monoterpenoids. Crit Rev Oncogenesis 1994;5:1–22.PubMedGoogle Scholar
  10. 10.
    Reddy BS, Wang C-X, Samalha H, et al. Chemoprevention of colon carcinogenesis by dietary perilly alcohol. Cancer Res 1997;57:420–425.PubMedGoogle Scholar
  11. 11.
    Huanbiao LH, Hadisusilo S, Qureshi AA, and Elson CE. Isopreniods suppress the growth of murine B16 melanoma in vitro and in vivo. J Nutr 1997;127:668–674.Google Scholar
  12. 12.
    Mills J, Chari R, Boyer I, Gould M, Jirtle R. Induction of apoptosis in liver tumors by the monopterene perilly alcohol. Cancer Res 1995;55:979–83.PubMedGoogle Scholar
  13. 13.
    Ariazi E, Salomi Y, Ellis M, et al. Activation of the transforming growth factor β signaling pathway and induction of cytostasis and apoptosis in mammary carcinoma treated with the anticancer agent perilly alcohol. Cancer Res 1999;59:1917–1928.PubMedGoogle Scholar
  14. 14.
    Crowell PL, Chang RR, Ren Z, Elson C, Gould MN. Selective inhibition of isoprenylylation of 21–26 kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 1991;266:17,679–17,685.Google Scholar
  15. 15.
    Ripple G, Gould M, Aroomanian R, et al. Phase I clinical and pharmacokinetic study of perilly alcohol administered four times a day. Clin Ca Res 2000;6(2):390–396.Google Scholar
  16. 16.
    Hudes GR, Szarka CE, Adama A, et al. Phase I pharmacokinetic trial of perilly alcohol (NSC 641066) in patients with refractory solid malignancy. Clin Ca Res Vol 2000;6(8):3071–3080.Google Scholar
  17. 17.
    Ripple GH, Gould MN, Stewart JA, et al. Phase I clinical trial of perilly alcohol administered daily. Clin Ca Res 2000;4(5):1159–1164.Google Scholar
  18. 18.
    Crowell PL. Monoterpenes in breast cancer chemoprevention. Breast Cancer Research and Treatment 1997;46:191–197.PubMedCrossRefGoogle Scholar
  19. 19.
    Kato K, Cox AD, Hiska MM, Graham SM, Buss JE, Der CJ. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 1992;89:6403–6407.PubMedCrossRefGoogle Scholar
  20. 20.
    Huluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer 2002;38:1685–1700.CrossRefGoogle Scholar
  21. 21.
    Gelb MH, Tamamoi F, Yokoyama K, Ghomashchi F, Esson K, Gould MN. The inhibition of protein prenyltransferases by oxygenated metabolites of limone and perillyl alcohol. Cancer Lett 1995;91:169–175.PubMedCrossRefGoogle Scholar
  22. 22.
    Eummer JT, Gibbs BS, Zahn TJ, Sebolt-Leopold JS, Gibbs R. Novel limonene phosphonate and farnesyl diphosphate analogues: design, synthesis and evaluation as potential protein-farnesyl transferase inhibitors. Bioorg Med Chem 1999;7:241–250.PubMedCrossRefGoogle Scholar
  23. 23.
    Hohl RJ. Monoterpenes as regulators of malignant cell proliferation. Advances in Exp Med and Bio 1996;401:137–146.Google Scholar
  24. 24.
    Lantry LE, Zhang Z, Crist KA, et al. Chemopreventive efficacy of promising farnesyl transferase inhibitors. Exp Lung Res 2000;26:773–790.PubMedCrossRefGoogle Scholar
  25. 25.
    Bailey HH, Levy D, Harris LS, et al. A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: Eastern Cooperative Oncology Group Study E2E96. Gynecologic Oncology 2002;85:464–468.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Sherry Morgan Meadows
    • 1
    Email author
  • Daniel Mulkerin
    • 1
  • Jordan Berlin
    • 2
  • Howard Bailey
    • 1
  • Jill Kolesar
    • 3
  • Deb Warren
    • 1
  • James P. Thomas
    • 1
  1. 1.Department of Medicine, Division of Medical OncologyThe University of WisconsinMadison
  2. 2.Department of Medicine, Division of Medical OncologyVanderbilt UniversityNashville
  3. 3.School of PharmacyThe University of WisconsinMadison

Personalised recommendations