Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1991 Aug;64(2):361–364. doi: 10.1038/bjc.1991.307

A phase II study of epidoxorubicin in colorectal cancer and the use of cyclosporin-A in an attempt to reverse multidrug resistance.

J Verweij 1, H Herweijer 1, R Oosterom 1, M E van der Burg 1, A S Planting 1, C Seynaeve 1, G Stoter 1, K Nooter 1
PMCID: PMC1977533  PMID: 1892765

Abstract

We determined the ability of the multidrug resistance (MDR) reversal agent cyclosporin-A to increase anthracycline drug accumulation in colorectal tumour cells in vitro, using the technique of on-line flow cytometry. Data of four previously untreated patients showed that cyclosporin-A can increase intracellular net-uptake of daunorubicin. A phase II study was initiated in 24 colorectal cancer patients. They received cyclosporin-A at a dose of 3 mg kg-1 over 1 h as i.v. infusion, at 7 h and at 1 h preceding cytotoxic drug administration. At the end of the second cyclosporin-A administration epidoxorubicin 90 mg m-2 was administered as i.v. bolus. Cycles were repeated every 3 weeks. Median cyclosporin-A peak blood levels and levels at 18 h after cytotoxic drug administration appeared to be 6248 ng ml-1 and 1012 ng ml-1 respectively. Only one partial response was observed, despite these high cyclosporin-A levels. Cyclosporin-A did not cause major toxicity, only a 29% incidence of hot flushes was observed. Epidoxorubicin toxicities were as expected but the frequency of severe leucocytopenia was striking. This treatment schedule can not be considered active in colorectal cancer.

Full text

PDF
361

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cairo M. S., Siegel S., Anas N., Sender L. Clinical trial of continuous infusion verapamil, bolus vinblastine, and continuous infusion VP-16 in drug-resistant pediatric tumors. Cancer Res. 1989 Feb 15;49(4):1063–1066. [PubMed] [Google Scholar]
  2. Chlebowski R. T., Silverberg I., Pajak T., Weiner J., Kardinal C., Bateman J. R. Treatment of advanced colon cancer with 5-fluorouracil (NSC19893) versus cyclophosphamide (NSC26271) plus 5-fluorouracil: prognostic aspects of the differential white blood cell count. Cancer. 1980 May 1;45(9):2240–2244. doi: 10.1002/1097-0142(19800501)45:9<2240::aid-cncr2820450903>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  3. Doroshow J. H., Multhauf P., Leong L., Margolin K., Litchfield T., Akman S., Carr B., Bertrand M., Goldberg D., Blayney D. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol. 1990 Mar;8(3):491–501. doi: 10.1200/JCO.1990.8.3.491. [DOI] [PubMed] [Google Scholar]
  4. Erlichman C., Fine S., Wong A., Elhakim T. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol. 1988 Mar;6(3):469–475. doi: 10.1200/JCO.1988.6.3.469. [DOI] [PubMed] [Google Scholar]
  5. Figueredo A., Arnold A., Goodyear M., Findlay B., Neville A., Normandeau R., Jones A. Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer. A phase I/II study. Cancer. 1990 May 1;65(9):1895–1902. doi: 10.1002/1097-0142(19900501)65:9<1895::aid-cncr2820650904>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  6. Ford J. M., Hait W. N. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev. 1990 Sep;42(3):155–199. [PubMed] [Google Scholar]
  7. Frishman W., Kirsten E., Klein M., Pine M., Johnson S. M., Hillis L. D., Packer M., Kates R. Clinical relevance of verapamil plasma levels in stable angina pectoris. Am J Cardiol. 1982 Nov;50(5):1180–1184. doi: 10.1016/0002-9149(82)90440-4. [DOI] [PubMed] [Google Scholar]
  8. Goldstein L. J., Galski H., Fojo A., Willingham M., Lai S. L., Gazdar A., Pirker R., Green A., Crist W., Brodeur G. M. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst. 1989 Jan 18;81(2):116–124. doi: 10.1093/jnci/81.2.116. [DOI] [PubMed] [Google Scholar]
  9. Herweijer H., van den Engh G., Nooter K. A rapid and sensitive flow cytometric method for the detection of multidrug-resistant cells. Cytometry. 1989 Jul;10(4):463–468. doi: 10.1002/cyto.990100415. [DOI] [PubMed] [Google Scholar]
  10. Holt D. W., Johnston A., Marsden J. T., Vernillet L., Keown P. A., Rosano T. G., Shaw L. M., Rosenthaler J. Monoclonal antibodies for radioimmunoassay of cyclosporine: a multicenter comparison of their performance with the Sandoz polyclonal radioimmunoassay kit. Clin Chem. 1988 Jun;34(6):1091–1096. [PubMed] [Google Scholar]
  11. Klohs W. D., Steinkampf R. W. Possible link between the intrinsic drug resistance of colon tumors and a detoxification mechanism of intestinal cells. Cancer Res. 1988 Jun 1;48(11):3025–3030. [PubMed] [Google Scholar]
  12. Moertel C. G. Chemotherapy of gastrointestinal cancer. N Engl J Med. 1978 Nov 9;299(19):1049–1052. doi: 10.1056/NEJM197811092991906. [DOI] [PubMed] [Google Scholar]
  13. Nooter K., Oostrum R., Jonker R., van Dekken H., Stokdijk W., van den Engh G. Effect of cyclosporin A on daunorubicin accumulation in multidrug-resistant P388 leukemia cells measured by real-time flow cytometry. Cancer Chemother Pharmacol. 1989;23(5):296–300. doi: 10.1007/BF00292407. [DOI] [PubMed] [Google Scholar]
  14. Nooter K., van den Engh G., Sonneveld P. Quantitative flow cytometric determination of anthracycline content of rat bone marrow cells. Cancer Res. 1983 Nov;43(11):5126–5130. [PubMed] [Google Scholar]
  15. Ozols R. F., Cowan K. New aspects of clinical drug resistance: the role of gene amplification and the reversal of resistance in drug refractory cancer. Important Adv Oncol. 1986:129–157. [PubMed] [Google Scholar]
  16. Ozols R. F., Cunnion R. E., Klecker R. W., Jr, Hamilton T. C., Ostchega Y., Parrillo J. E., Young R. C. Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol. 1987 Apr;5(4):641–647. doi: 10.1200/JCO.1987.5.4.641. [DOI] [PubMed] [Google Scholar]
  17. Pastan I., Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med. 1987 May 28;316(22):1388–1393. doi: 10.1056/NEJM198705283162207. [DOI] [PubMed] [Google Scholar]
  18. Shen D. W., Fojo A., Chin J. E., Roninson I. B., Richert N., Pastan I., Gottesman M. M. Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science. 1986 May 2;232(4750):643–645. doi: 10.1126/science.3457471. [DOI] [PubMed] [Google Scholar]
  19. Silbermann M. H., Boersma A. W., Janssen A. L., Scheper R. J., Herweijer H., Nooter K. Effects of cyclosporin A and verapamil on the intracellular daunorubicin accumulation in Chinese hamster ovary cells with increasing levels of drug-resistance. Int J Cancer. 1989 Oct 15;44(4):722–726. doi: 10.1002/ijc.2910440428. [DOI] [PubMed] [Google Scholar]
  20. Slater L. M., Sweet P., Stupecky M., Wetzel M. W., Gupta S. Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer. 1986 Aug;54(2):235–238. doi: 10.1038/bjc.1986.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sonneveld P., Nooter K. Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia. Br J Haematol. 1990 Jun;75(2):208–211. doi: 10.1111/j.1365-2141.1990.tb02650.x. [DOI] [PubMed] [Google Scholar]
  22. Twentyman P. R., Fox N. E., White D. J. Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cell line. Br J Cancer. 1987 Jul;56(1):55–57. doi: 10.1038/bjc.1987.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wadler S., Schwartz E. L., Goldman M., Lyver A., Rader M., Zimmerman M., Itri L., Weinberg V., Wiernik P. H. Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol. 1989 Dec;7(12):1769–1775. doi: 10.1200/JCO.1989.7.12.1769. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES