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.
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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: 1484
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: 133
Borner MM, Kneer J, Crevoisier C, Brunner KW, Cerny T (1993) Biovailability and feasibility of subcutaneous 5-fluorouracil. Br J Cancer 68: 537
Boucher Y, Baxter LT, Jain RK (1990) Intersititial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50: 4478
Brambilla L, Boneschi V, Beretta G, Finzi AF (1984) Intralesional chemotherapy for Kaposi's sarcoma. Dermatologica 169: 150
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: 539
Cohen KL, Brown RE (1978) High-performance liquid chromatographic analysis of 5-fluorouracil in plasma. J Chromatogr 151: 237
Cooperman LS, Mackinnon V, Bechler G, Pharriss BB (1985) Injectable collagen: a six-year clinical investigation. Aesthetic Plast Surg 9: 145.
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: 2446
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 46:4886
Drewinko B, Yang L (1985) Cellular basis for the inefficacy of 5-FU in human colon carcinoma. Cancer Treat Rep 69: 1391
Figueroa S, Gennaro A (1980) Intralesional bleomycin injection in treatment of condyloma acuminatum. Dis Colon Rectum 23: 550
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: 4288
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: 5384
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: 533
Goette DK, Odom RB (1980) Successful treatment of keratoacanthoma with intralesional fluorouracil. J Am Acad Dermatol 2: 212
Goette DK, Odom RB, Owens R (1977) Allergic contact dermatitis from topical fluorouracil. Arch Dermatol 113: 196
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: 437
Hanker JS, Giammard BL (1988) Biomaterials and biomedical devices. Science 242: 885
Hashimoto Y, Suzuki S (1992) Basic approach to application of liposomes for cancer chemotherapy. Tohoku J Exp Med 168: 361
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: 724
Hayes ME, O'Keefe EJ (1986) Reduced dose of bleomycin in the treatment of recalcitrant warts. J Am Acad Dermatol 15: 1002
Howes A, Herman T, Montoya V (1988) Effects of matrix-associated chemotherapy in combination with irradiation in vivo. NCI Monogr 6: 141
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: 4357
Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48: 2641
Kato T, Nemoto R, Mori H, Tahahashi M, Tamakawa Y, Harada M (1981) Arterial chemoembolization with microencapsulated anticancer drug. JAMA 245: 11231
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: 229
Koenig RD, Horowitz LR (1982) Verrucae plantaris—effective treatment with bleomycin: review of literature and case presentations. J Foot Surg 21: 108
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: 83
Kurtis B, Rosen T (1980) Treatment of cutaneous neoplasms by intralesional injections of 5-fluorouracil (5-FU). J Dermatol Surg Oncol 6: 122
MacMillan WE, Wolberg WH, Welling PG (1978) Pharmacokinetics of fluorouracil in humans. Cancer Res 38: 3479
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 1–38
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: 561
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: 723
Rootman J, Ostry A, Gudauskas G (1984) Pharmacokinetics and metabolism of 5-fluorouracil following subconjunctival versus intravenous administration. Can J Ophthalmol 19: 187
Scolaro M, Kennedy P, Blayney DW, Flanagan B, Lisak J, Presant J (1993) Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet 341: 1242
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: 459
Stenzel KH, Miyata T, Rubin AL (1974) Collagen as a biomaterial. Annu Rev Biophys Bioeng 3: 231
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: 35
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: 329
Thomlinson F (1983) Microsphere delivery systems for drug targeting and controlled release. Br J Pharm Tech Prod Mfr 4: 49
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: 595
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: 272
Yu N, Conley F, Luck EE, Brown DM (1988) Response of murine tumor to matrix-associated cisplatin intratumoral implants. NCI Monogr 6: 137
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Yu, N.Y., Orenberg, E.K., Luck, E.E. et al. Antitumor effect of intratumoral administration of fluorouracil/epinephrine injectable gel in C3H mice. Cancer Chemother. Pharmacol. 36, 27–34 (1995). https://doi.org/10.1007/BF00685728
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DOI: https://doi.org/10.1007/BF00685728