Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1995 Mar;71(3):482–488. doi: 10.1038/bjc.1995.98

Pharmacology of liposomal vincristine in mice bearing L1210 ascitic and B16/BL6 solid tumours.

L D Mayer 1, D Masin 1, R Nayar 1, N L Boman 1, M B Bally 1
PMCID: PMC2033637  PMID: 7880728

Abstract

Vincristine pharmacokinetic, tumour uptake and therapeutic characteristics were investigated here in order to elucidate the processes underlying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated more than 100-fold in the liposomal formulation compared with free drug in tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodistribution studies demonstrate that the extent and duration of tumour exposure to vincristine is dramatically improved when the drug is administered i.v. in liposomal form. Specifically, 72 h trapezoidal area under the curve values for liposomal vincristine in the murine L1210 ascitic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respectively, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in significant inhibition of tumour growth, whereas no anti-tumour activity is observed with free vincristine. Comparisons of drug and liposomal lipid accumulation in tumour and muscle tissue indicate that the enhanced efficacy of liposomal vincristine is related predominantly to drug delivered by liposomes to the tumour site rather than drug released from liposomes in the circulation. Consequently, improvements in liposomal vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug retention in the circulation.

Full text

PDF
482

Selected References

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

  1. Allen T. M., Mehra T., Hansen C., Chin Y. C. Stealth liposomes: an improved sustained release system for 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1992 May 1;52(9):2431–2439. [PubMed] [Google Scholar]
  2. Bally M. B., Masin D., Nayar R., Cullis P. R., Mayer L. D. Transfer of liposomal drug carriers from the blood to the peritoneal cavity of normal and ascitic tumor-bearing mice. Cancer Chemother Pharmacol. 1994;34(2):137–146. doi: 10.1007/BF00685931. [DOI] [PubMed] [Google Scholar]
  3. Boman N. L., Masin D., Mayer L. D., Cullis P. R., Bally M. B. Liposomal vincristine which exhibits increased drug retention and increased circulation longevity cures mice bearing P388 tumors. Cancer Res. 1994 Jun 1;54(11):2830–2833. [PubMed] [Google Scholar]
  4. Cowens J. W., Creaven P. J., Greco W. R., Brenner D. E., Tung Y., Ostro M., Pilkiewicz F., Ginsberg R., Petrelli N. Initial clinical (phase I) trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res. 1993 Jun 15;53(12):2796–2802. [PubMed] [Google Scholar]
  5. Forssen E. A., Coulter D. M., Proffitt R. T. Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res. 1992 Jun 15;52(12):3255–3261. [PubMed] [Google Scholar]
  6. Gabizon A. A. Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res. 1992 Feb 15;52(4):891–896. [PubMed] [Google Scholar]
  7. Gabizon A., Catane R., Uziely B., Kaufman B., Safra T., Cohen R., Martin F., Huang A., Barenholz Y. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994 Feb 15;54(4):987–992. [PubMed] [Google Scholar]
  8. Gabizon A., Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6949–6953. doi: 10.1073/pnas.85.18.6949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gerlowski L. E., Jain R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc Res. 1986 May;31(3):288–305. doi: 10.1016/0026-2862(86)90018-x. [DOI] [PubMed] [Google Scholar]
  10. Gondal J. A., Preuss H. G., Swartz R., Rahman A. Comparative pharmacological, toxicological and antitumoral evaluation of free and liposome-encapsulated cisplatin in rodents. Eur J Cancer. 1993;29A(11):1536–1542. doi: 10.1016/0959-8049(93)90290-v. [DOI] [PubMed] [Google Scholar]
  11. Hengge U. R., Brockmeyer N. H., Baumann M., Reimann G., Goos M. Liposomal doxorubicin in AIDS-related Kaposi's sarcoma. Lancet. 1993 Aug 21;342(8869):497–497. doi: 10.1016/0140-6736(93)91624-u. [DOI] [PubMed] [Google Scholar]
  12. Heuser L. S., Miller F. N. Differential macromolecular leakage from the vasculature of tumors. Cancer. 1986 Feb 1;57(3):461–464. doi: 10.1002/1097-0142(19860201)57:3<461::aid-cncr2820570310>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  13. Horton J. K., Houghton P. J., Houghton J. A. Relationships between tumor responsiveness, vincristine pharmacokinetics and arrest of mitosis in human tumor xenografts. Biochem Pharmacol. 1988 Oct 15;37(20):3995–4000. doi: 10.1016/0006-2952(88)90085-8. [DOI] [PubMed] [Google Scholar]
  14. Huang S. K., Lee K. D., Hong K., Friend D. S., Papahadjopoulos D. Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. Cancer Res. 1992 Oct 1;52(19):5135–5143. [PubMed] [Google Scholar]
  15. Huang S. K., Martin F. J., Jay G., Vogel J., Papahadjopoulos D., Friend D. S. Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene. Am J Pathol. 1993 Jul;143(1):10–14. [PMC free article] [PubMed] [Google Scholar]
  16. Huang S. K., Mayhew E., Gilani S., Lasic D. D., Martin F. J., Papahadjopoulos D. Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. Cancer Res. 1992 Dec 15;52(24):6774–6781. [PubMed] [Google Scholar]
  17. Jackson D. V., Jr, Bender R. A. Cytotoxic thresholds of vincristine in a murine and a human leukemia cell line in vitro. Cancer Res. 1979 Nov;39(11):4346–4349. [PubMed] [Google Scholar]
  18. Mayer L. D., Bally M. B., Cullis P. R., Wilson S. L., Emerman J. T. Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett. 1990 Sep;53(2-3):183–190. doi: 10.1016/0304-3835(90)90212-g. [DOI] [PubMed] [Google Scholar]
  19. Mayer L. D., Bally M. B., Loughrey H., Masin D., Cullis P. R. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res. 1990 Feb 1;50(3):575–579. [PubMed] [Google Scholar]
  20. Mayer L. D., Hope M. J., Cullis P. R., Janoff A. S. Solute distributions and trapping efficiencies observed in freeze-thawed multilamellar vesicles. Biochim Biophys Acta. 1985 Jul 11;817(1):193–196. doi: 10.1016/0005-2736(85)90084-7. [DOI] [PubMed] [Google Scholar]
  21. Mayer L. D., Hope M. J., Cullis P. R. Vesicles of variable sizes produced by a rapid extrusion procedure. Biochim Biophys Acta. 1986 Jun 13;858(1):161–168. doi: 10.1016/0005-2736(86)90302-0. [DOI] [PubMed] [Google Scholar]
  22. Mayer L. D., Nayar R., Thies R. L., Boman N. L., Cullis P. R., Bally M. B. Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia. Cancer Chemother Pharmacol. 1993;33(1):17–24. doi: 10.1007/BF00686017. [DOI] [PubMed] [Google Scholar]
  23. Mayer L. D., Tai L. C., Ko D. S., Masin D., Ginsberg R. S., Cullis P. R., Bally M. B. Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 1989 Nov 1;49(21):5922–5930. [PubMed] [Google Scholar]
  24. Money-Kyrle J. F., Bates F., Ready J., Gazzard B. G., Phillips R. H., Boag F. C. Liposomal daunorubicin in advanced Kaposi's sarcoma: a phase II study. Clin Oncol (R Coll Radiol) 1993;5(6):367–371. doi: 10.1016/s0936-6555(05)80088-3. [DOI] [PubMed] [Google Scholar]
  25. Perez-Soler R., Han I., al-Baker S., Khokhar A. R. Lipophilic platinum complexes entrapped in liposomes: improved stability and preserved antitumor activity with complexes containing linear alkyl carboxylato leaving groups. Cancer Chemother Pharmacol. 1994;33(5):378–384. doi: 10.1007/BF00686266. [DOI] [PubMed] [Google Scholar]
  26. Perez-Soler R., Ling Y. H., Zou Y., Priebe W. Cellular pharmacology of the partially non-cross-resistant anthracycline annamycin entrapped in liposomes in KB and KB-V1 cells. Cancer Chemother Pharmacol. 1994;34(2):109–118. doi: 10.1007/BF00685927. [DOI] [PubMed] [Google Scholar]
  27. Schwendener R. A., Fiebig H. H., Berger M. R., Berger D. P. Evaluation of incorporation characteristics of mitoxantrone into unilamellar liposomes and analysis of their pharmacokinetic properties, acute toxicity, and antitumor efficacy. Cancer Chemother Pharmacol. 1991;27(6):429–439. doi: 10.1007/BF00685156. [DOI] [PubMed] [Google Scholar]
  28. Storm G., Steerenberg P. A., Emmen F., van Borssum Waalkes M., Crommelin D. J. Release of doxorubicin from peritoneal macrophages exposed in vivo to doxorubicin-containing liposomes. Biochim Biophys Acta. 1988 May 12;965(2-3):136–145. doi: 10.1016/0304-4165(88)90049-9. [DOI] [PubMed] [Google Scholar]
  29. Vaage J., Donovan D., Mayhew E., Uster P., Woodle M. Therapy of mouse mammary carcinomas with vincristine and doxorubicin encapsulated in sterically stabilized liposomes. Int J Cancer. 1993 Jul 30;54(6):959–964. doi: 10.1002/ijc.2910540616. [DOI] [PubMed] [Google Scholar]
  30. Yuan F., Leunig M., Huang S. K., Berk D. A., Papahadjopoulos D., Jain R. K. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 1994 Jul 1;54(13):3352–3356. [PubMed] [Google Scholar]

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

RESOURCES