Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 1, pp 27–34 | Cite as

Antitumor effect of intratumoral administration of fluorouracil/epinephrine injectable gel in C3H mice

  • Ning Y. Yu
  • Elaine K. Orenberg
  • Edward E. Luck
  • Dennis M. Brown
Original Article Fluorouracil, Intratumoral Injection, In Vivo Efficacy

Abstract

Fluorouracil/epinephrine injectable gel (5-FU/epi gel) was evaluated in vitro for its drug-release profile characteristics and in a mouse tumor model for its antitumor effectiveness. In vitro chemosensitivity studies with 5-FU in RIF-1 fibrosarcoma cells showed less than 1 log cell kill at 1 mM after 2 h of exposure. Increasing the exposure time to 24 h resulted in greater cell killing (∼ 2.5 log cell kill at 0.5 mM), suggesting that sustained drug levels in tumors would result in an increased efficacy outcome in vivo. A 5-FU/epi injectable gel was designed, providing drug release in vitro of 50% by ∼ 4 h and of 80% by 24 h. The retention of 5-FU in RIF-1 mouse tumors was determined after intratumoral administration of 5-FU/epi gel or various combinations of the formulation components. Area-under-the-curve (AUC0–24 h) calculations resulted in an AUC value of 146.4% h for the 5-FU/epi gel formulation as compared with 45.7% h for 5-FU solution. Tumor growth was significantly delayed (P<0.05) with the 5=FU/epi gel (60 mg/kg) as compared with 5-FU solution given intratumorally or systemically. A fluorouracil dose of 150 mg/kg in the 5-FU/epi gel given weekly for 13 weeks was not lethally toxic, whereas the same dose given as drug solution was 100% lethal, suggesting that the therapeutic index for 5-FU in the gel formulation may be much greater than that for aqueous drug solution delivered intratumorally.

Key words

Fluorouracil Intratumoral injection In vivo efficacy 

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References

  1. 1.
    Ahmad I, Longenecker M, Samuel J, Allen TM (1993) Antibody-targeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice. Cancer Res 53: 1484Google Scholar
  2. 2.
    Begg AC, Bartelink H, Stewart FA, Brown DM, Luck EE (1988) Improvement of differential toxicity between tumor and normal tissues using intratumoral injection with or without a slow-release matrix system. NCI Monogr 6: 133Google Scholar
  3. 3.
    Borner MM, Kneer J, Crevoisier C, Brunner KW, Cerny T (1993) Biovailability and feasibility of subcutaneous 5-fluorouracil. Br J Cancer 68: 537Google Scholar
  4. 4.
    Boucher Y, Baxter LT, Jain RK (1990) Intersititial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50: 4478Google Scholar
  5. 5.
    Brambilla L, Boneschi V, Beretta G, Finzi AF (1984) Intralesional chemotherapy for Kaposi's sarcoma. Dermatologica 169: 150Google Scholar
  6. 6.
    Codde JP, Lumsden AJ, Napoli S, Burton MA, Gray BN (1993) A comparative study of the anticancer efficacy of doxorubicin carrying microspheres and liposomes using a rat liver tumor model. Anticancer Res 13: 539Google Scholar
  7. 7.
    Cohen KL, Brown RE (1978) High-performance liquid chromatographic analysis of 5-fluorouracil in plasma. J Chromatogr 151: 237Google Scholar
  8. 8.
    Cooperman LS, Mackinnon V, Bechler G, Pharriss BB (1985) Injectable collagen: a six-year clinical investigation. Aesthetic Plast Surg 9: 145.Google Scholar
  9. 9.
    Daniels JR, Sternlicht M, Daniels AM (1988) Collagen chemoembolization: pharmacokinetics and tissue tolerance ofcis-diamminedichloroplatinum(II) in porcine liver and rabbit kidney. Cancer Res 48: 2446Google Scholar
  10. 10.
    Dillman RO, Shawler DL, Johnson DE, Meyer DL, Koziol JA, Frincke JM (1986) Preclinical trials with combinations and conjugates of T101 monoclonal antibody and doxorubicin. Cancer Res 46:4886Google Scholar
  11. 11.
    Drewinko B, Yang L (1985) Cellular basis for the inefficacy of 5-FU in human colon carcinoma. Cancer Treat Rep 69: 1391Google Scholar
  12. 12.
    Figueroa S, Gennaro A (1980) Intralesional bleomycin injection in treatment of condyloma acuminatum. Dis Colon Rectum 23: 550Google Scholar
  13. 13.
    FitzGerald DJ, Willingham MC, Cardarelli CO, Hamada H, Tsuruo T, Gottesman MM, Pastan I (1987) A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc Natl Acad Sci USA 84: 4288Google Scholar
  14. 14.
    Fournier C, Hecquet B, Bouffard P, Vert M, Caty A, Vilain M-O, Vanseymortier L, Merle S, Krikorian A, Lefebvre J-L, Delobelle A, Adenis L (1991) Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors. Cancer Res 51: 5384Google Scholar
  15. 15.
    Friedman-Kien AE, Eron LJ, Conant M, Growdon W, Badiak H, Bradstreet PW, Fedorozyk D, Trout JR, Plasse TF (1988) Natural interferon for treatment of condylomata acuminata. JAMA 259: 533Google Scholar
  16. 16.
    Goette DK, Odom RB (1980) Successful treatment of keratoacanthoma with intralesional fluorouracil. J Am Acad Dermatol 2: 212Google Scholar
  17. 17.
    Goette DK, Odom RB, Owens R (1977) Allergic contact dermatitis from topical fluorouracil. Arch Dermatol 113: 196Google Scholar
  18. 18.
    Greenway HT, Cornell RC, Tanner DJ, Peels E, Bordin GM, Nagi C (1986) Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol 15: 437Google Scholar
  19. 19.
    Hanker JS, Giammard BL (1988) Biomaterials and biomedical devices. Science 242: 885Google Scholar
  20. 20.
    Hashimoto Y, Suzuki S (1992) Basic approach to application of liposomes for cancer chemotherapy. Tohoku J Exp Med 168: 361Google Scholar
  21. 21.
    Hata Y, Takada N, Sasaki F, Abe T, Hamada H, Takahashi H, Uchino J, Tsukada Y (1992) Immunotargeting chemotherapy for AFP-producing pediatric liver cancer using the conjugates of anti-AFP antibody and anti-tumor agents. J Pediatr Surg 27: 724Google Scholar
  22. 22.
    Hayes ME, O'Keefe EJ (1986) Reduced dose of bleomycin in the treatment of recalcitrant warts. J Am Acad Dermatol 15: 1002Google Scholar
  23. 23.
    Howes A, Herman T, Montoya V (1988) Effects of matrix-associated chemotherapy in combination with irradiation in vivo. NCI Monogr 6: 141Google Scholar
  24. 24.
    Ichihara T, Sakamoto K, Mori K, Akagi M (1989) Transcatheter arterial chemoembolization therapy for hepatocellular carcinoma using polylactic acid micropheres containing aclarubicin hydrochloride. Cancer Res 49: 4357Google Scholar
  25. 25.
    Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48: 2641Google Scholar
  26. 26.
    Kato T, Nemoto R, Mori H, Tahahashi M, Tamakawa Y, Harada M (1981) Arterial chemoembolization with microencapsulated anticancer drug. JAMA 245: 11231Google Scholar
  27. 27.
    Kitchell BK, Brown DM, Luck EE, Woods LL, Orenberg EK, Bloch DA (1994) Intralesional therapeutic implant for the treatment of primary oral malignant melanoma in the dog. J Am Vet Med Assoc 204: 229Google Scholar
  28. 28.
    Koenig RD, Horowitz LR (1982) Verrucae plantaris—effective treatment with bleomycin: review of literature and case presentations. J Foot Surg 21: 108Google Scholar
  29. 29.
    Krag D, Theon AP, Schneider PD, Goodnight JE (1900) Intralesionalcis-diamminedichloroplatinum and purified collagen treatment of human metastatic malignancies: a feasibility study. J Surg Oncol 43: 83Google Scholar
  30. 30.
    Kurtis B, Rosen T (1980) Treatment of cutaneous neoplasms by intralesional injections of 5-fluorouracil (5-FU). J Dermatol Surg Oncol 6: 122Google Scholar
  31. 31.
    MacMillan WE, Wolberg WH, Welling PG (1978) Pharmacokinetics of fluorouracil in humans. Cancer Res 38: 3479Google Scholar
  32. 32.
    Nimni ME, Cheung DT, Strate B, Kodama M, Sheikh K (1988) Bioprosthesis derived from cross-linked and chemically modified collagenous tissues. In: Nimni ME, Luck JV (eds) Collagen, vol III. Biotechnology, CRC, Boca Raton, Florida, pp 1–38Google Scholar
  33. 33.
    Orenberg EK, Luck EE, Brown DM, Kitchel BE (1992) Implant delivery system. Intralesional delivery of chemotherapeutic agents for treatment of spontaneous skin tumors in veterinary patients. Clin in Dermatol 9: 561Google Scholar
  34. 34.
    Orenberg EK, Miller BH, Greenway HT, Koperski JA, Lowe N, Rosen T, Brown DM, Inui M, Korey AG, Luck EE (1992) The effect of intralesional 5-fluorouracil therapeutic implant (MPI 5003) for treatment of basal cell carcinoma. J Am Acad Dermatol 27: 723Google Scholar
  35. 35.
    Rootman J, Ostry A, Gudauskas G (1984) Pharmacokinetics and metabolism of 5-fluorouracil following subconjunctival versus intravenous administration. Can J Ophthalmol 19: 187Google Scholar
  36. 36.
    Scolaro M, Kennedy P, Blayney DW, Flanagan B, Lisak J, Presant J (1993) Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet 341: 1242Google Scholar
  37. 37.
    Spicer DV, Ardalan B, Daniels JR, Silberman H, Johnson K (1988) Reevaluation of the maximum tolerated dose of continuous venous infusion of 5-fluorouracil with pharmacokinetics. Cancer Res 48: 459Google Scholar
  38. 38.
    Stenzel KH, Miyata T, Rubin AL (1974) Collagen as a biomaterial. Annu Rev Biophys Bioeng 3: 231Google Scholar
  39. 39.
    Sutton R, Yu N, Luck E, Brown D, Conley F (1990) Reduction of vinblastine neurotoxicity in mice utilizing a collagen matrix carrier. Selective Cancer Ther 6: 35Google Scholar
  40. 40.
    Tamargo RJ, Myseros JS, Epstein JI, Yang MB, Chasin M, Brem H (1993) Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain. Cancer Res 53: 329Google Scholar
  41. 41.
    Thomlinson F (1983) Microsphere delivery systems for drug targeting and controlled release. Br J Pharm Tech Prod Mfr 4: 49Google Scholar
  42. 42.
    Twentyman PR, Brown JM, Gray JW, Franko AJ, Scoles MA, Kallman RF (1980) A new mouse tumor model system (RIF-1) for comparison of end-point studies. J Natl Cancer Inst 64: 595Google Scholar
  43. 43.
    Vance JC, Bart BJ, Hansen RC, Reichman RC, McEwen C, Hatch KD, Berman B, Tanner DJ (1986) Intralesional recombinant alpha-2 interferon for treatment of patients with condyloma acuminatum or verruca plantaris. Arch Dermatol 122: 272Google Scholar
  44. 44.
    Yu N, Conley F, Luck EE, Brown DM (1988) Response of murine tumor to matrix-associated cisplatin intratumoral implants. NCI Monogr 6: 137Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Ning Y. Yu
    • 1
  • Elaine K. Orenberg
    • 1
  • Edward E. Luck
    • 1
  • Dennis M. Brown
    • 1
  1. 1.Matrix Pharmaceutical, Inc.Menlo ParkUSA

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