Cancer Chemotherapy and Pharmacology

, Volume 34, Issue 6, pp 527–534 | Cite as

Interaction of liposome-associated all-trans-retinoic acid with squamous carcinoma cells

  • Ranjani Parthasarathy
  • Peter G. Sacks
  • Daniel Harris
  • Heidi Brock
  • Kapil Mehta
Original Articles Liposomes, Retinoids, Squamous-cell Carcinoma, Transglutaminase


Because of their antiproliferative and differentiation-inducing properties, retinoids have been used clinically as therapeutic and chemopreventive agents against squamous-cell carcinomas (SCC). As is the case for many therapeutic agents, however, the administration of retinoids is associated with toxic effects. Because encapsulation of certain drugs in lipid vesicles (liposomes) has been shown to result in reduced toxic effects, we studied the in vitro interaction of liposome-encapsulated all-trans-retinoic acid (L-ATRA) with a SCC line (MDA 886Ln) and its multicellular tumor spheroid (MTS) model. Various L-ATRA formulations were tested for incorporation of retinoic acid, toxic effects against human red blood cells, uptake and retention by tumor cells, and anti-proliferative effects against SCC. Of the different formulations tested, L-ATRA containing diphosphatidyl palmitoylcholine (DPPC) and stearylamine (SA; 9:1, w/w) showed optimal drug incorporation, high stability, and minimal toxicity toward red blood cells and was highly efficacious in delivering ATRA and, thus, in inhibiting the growth of MDA 886Ln and its MTS model. DPPC: SA L-ATRA inhibited the expression of the enzyme keratinocyte transglutaminase in epidermal cells as effectively as did the free drug. These results suggest that liposomes can serve as an effective carrier system for the delivery of retinoids to SCC.

Key words

Liposomes Retinoids Squamous-cell carcinoma Transglutaminase 


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  1. 1.
    Breitman T, Selonic SE, Collins SJ (1980) Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA 77:2936Google Scholar
  2. 2.
    Burge-Bottenbly A, Shklar G (1983) Retardation of experimental oral cancer development by retinyl acetate. Nutr Cancer 5:121Google Scholar
  3. 3.
    Flynn PJ, Miller WJ, Weisdorf DJ, Arthur DC, Brunning R, Branda RF (1986) Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62:1211Google Scholar
  4. 4.
    Hansen MB, Nielsen SE, Berg K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 119:203Google Scholar
  5. 5.
    Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, Fofonoff S, Byers R, Atkinson N, Vaughan C, Toth BB, Kramer A, Dimery IW, Skipper P, Strong S (1986) 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315:1501Google Scholar
  6. 6.
    Jetten AM (1987) Multistep process of squamous differentiation of tracheobronchial epithelial cells: role of retinoids. Dermatologica 175:37Google Scholar
  7. 7.
    Jetten A, Kim J, Sacks P, Rearick JI, Lotan D, Hong WK, Lotan R (1990) Inhibition of growth and squamous-cell differentiation markers in cultured human head and neck squamous carcinoma cells by β-all-trans-retinoic acid. Int J Cancer 45:195Google Scholar
  8. 8.
    Lippman SM, Parkinson DR, Itri LM, Weber RS, Schantz SP, Ota DM, Schusterman MA, Krakoff IH, Gutterman JU, Hong WK (1992) 13-cis-Retinoic acid plus interferon α-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84:235Google Scholar
  9. 9.
    Lippman S, Kavanagh J, Paredes-Espinoza M, Delgadillo-Madrueno F, Paredes-Casillas P, Hong WK, Holdener E, Krakoff IH (1992) 13-cis Retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 84:241Google Scholar
  10. 10.
    Lotan R (1980) Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 605:33Google Scholar
  11. 11.
    Mehta K (1989) Interaction of liposome-encapsulated retinoids with normal and leukemic cells. In: Reichert U, Shroot B (eds) Pharmacology and skin. Karger, Basel, 74Google Scholar
  12. 12.
    Meng-er H, Ye Y, Shu-rong C, Jin-ren C, Jia-Xiang L, Lin Z, Long-jun G, Zhen-yi W (1988) Use ofall-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567Google Scholar
  13. 13.
    Mori S (1922) The changes in the para-ocular glands which follow the administration of diets low in fat-soluble A; with notes on the effect of the same diets on the salivary glands and the mucosa of the larynx and trachea. Bull Johns Hopkins Hosp 33:357Google Scholar
  14. 14.
    Nastruzzi C, Walde P, Menegatti E, Roberto G (1990) Liposome-associated retinoic acid: increased in vitro antiproliferative effects on neoplastic cells. FEBS Lett 259:293Google Scholar
  15. 15.
    Poddar S, Hong WK, Thacher S, Lotan R (1991) Retinoic acid suppression of squamous differentiation in human head-and-neck squamous carcinoma cells. Int J Cancer 48:239Google Scholar
  16. 16.
    Rahman A, More N, Schein PS (1982) Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration. Cancer Res 42:1817Google Scholar
  17. 17.
    Rahman A, Treat J, Roh J, Potkul LA, Alvord WG, Forst D, Woolley PV (1990) A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol 8:1093Google Scholar
  18. 18.
    Sacks PG (1988) Growth of head and neck squamous-cell carcinoma lines as multicellular tumor spheroids. In: Wolf GT, Carey TE (eds) Head and neck oncology research. Kugler and Ghedini, Berkeley, 3Google Scholar
  19. 19.
    Sacks PG, Oke V, Amos B, Vasey T, Lotan R (1989) Modulation of growth, differentiation and glycoprotein synthesis by β-all-trans-retinoic acid in a multicellular tumor spheroid model for squamous carcinoma of the head and neck. Int J Cancer 44:926Google Scholar
  20. 20.
    Sacks PG, Oke V, Vasey T, Lotan R (1989) Retinoic acid inhibition of a head and neck multicellular tumor spheroid model. Head Neck Surg 11:219Google Scholar
  21. 21.
    Sacks PG, Oke V, Calkins DP, Vasey T, Terry NHA (1990) Effects of β-all-trans-retinoic acid on growth, proliferation, and cell death in a multicellular tumor spheroid model for squamous carcinomas. J Cell Physiol 144:237Google Scholar
  22. 22.
    Sacks PG, Oke V, Mehta K (1992) Antiproliferative effects of free and liposome-encapsulated retinoic acid in a squamous carcinoma model: monolayer cells and multicellular tumor spheroids. Cancer Res Clin Oncol 118:490Google Scholar
  23. 23.
    Shklar G, Schwartz J, Grau D, Trickler DP, Wallace KD (1980) Inhibition of hamster buccal pouch carcinogenesis. Oral Surg 50:45Google Scholar
  24. 24.
    Silverman AK, Ellis CN, Voorhees JJ (1987) Hypervitaminosis A syndrome: a paradigm of retinoid side effects. J Am Acad Dermatol 16:1027Google Scholar
  25. 25.
    Weinstein JN, Leserman LD (1984) Liposomes as drug carriers in cancer chemotherapy. Pharm Ther 24:207Google Scholar
  26. 26.
    Yoshihara E, Nakae T (1986) Cytolytic activity of liposomes containing stearylamine. Biochim Biophys Acta 854:93Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Ranjani Parthasarathy
    • 1
  • Peter G. Sacks
    • 2
  • Daniel Harris
    • 2
  • Heidi Brock
    • 2
  • Kapil Mehta
    • 1
  1. 1.Department of Clinical InvestigationThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Head and NeckMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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