Summary
Bisantrene solubility and skin toxicity were studied in mice given intraperitoneal (IP) and intradermal (ID) drug respectively. Bisantrene (1 mg/ml) in 5% dextrose readily precipitated in the mouse peritoneum. The admixture of bisantrene into various lipophilic solvents did not reduce drug precipitation in vivo in the mouse or in vitro in human plasma at 37°C. Drug stability studies using high performance liquid chromatography (HPLC) showed markedly reduced bisantrene stability at alkaline pH. Bisantrene skin toxicity in BALB/c mice was characterized by ulceration which persisted for up to four months after ID injection. Skin toxicity was consistently reduced by dilute sodium bicarbonate injection into the bisantrene extravasation site. Three clinical extravasation cases treated with sodium bicarbonate showed no bisantrene ulceration. Ineffective local antidotes included sodium cromolyn, N-acetylcysteine, hydrocortisone, and heat (which appeared to increase toxicity).
Similar content being viewed by others
References
Von Hoff DD, Coltman CA, Forseth B: Activity of 9,10-anthracene dicarboxaldehyde bis (4,5-dihydro-1-H-imidazol-2-yl) hydrazone dihydrochloride (CL 216,942) in a human tumor cloning system. Cancer Chemother Pharmacol 6:141–144, 1981
Von Hoff DD, Myers JW, Kuhn J, Sandbach JF, Pocelinko R, Clark G, Coltman CA, Jr: Phase I clinical investigation of 9,10-anthracene dicarboxaldehyde bis (4,5-dihydro-1-H-imidazol-2–11) hydrazone dihydrochloride (CL 216,942). Cancer Res 41:3118–3121, 1981
Spiegel RJ, Blum RH, Levin M, Pinto CA, Wernz JC, Speyer JL, Hoffman KS, Muggia FM: Phase I clinical trial of 9,10-anthracene dicarboxaldehyde (bisantrene) admin istered in a five-day schedule. Cancer Res 42:354–358, 1982
Alberts DS, Mackel C, Pocelinko R, Salmon SE: Phase I clinical investigation of 9,10-anthracene dicarboxaldehyde bis (4,5-dihydro-1 H-imidazol-2-yl) hydrazone dihydrochloride with correlative in vitro human tumor clonogenic assay. Cancer Res 42:5472–5478, 1982
Powis G, Kovach JS: Disposition of bisantrene in humans and rabbits: evidence for intravascular deposition of drug as a cause of phlebitis. Cancer Res 43: 925–929, 1983
Peng Y-M, Davis TP, Alberts DS: High performance liquid chromatography of a new anticancer drug, ADCA-physicochemical properties and pharmacokinetics. Life Sci 29:361–369, 1981
Dorr RT, Alberts DS, Chen H-SG: Experimental model of doxorubicin extravasation in the mouse. J Pharmacol Meth 4:237–250, 1980
Alberts DS, Peng Y-M, Leigh S, Davis TP, Woodward DL: Pharmacokinetics of bisantrene in cancer patients. In CA Coltman and DD Von Hoff (eds): Proceedings of the 13th International Congress of Chemotherapy: Part 213, Symposium on Bisantrene. Verlag H. Egerman, Vienna, Austria, 1983, pp 29–33
Alberts DS, Peng YM, Davis TP: Comparative pharmacology of mitoxantrone and bisantrene. Clin Pharmacol Ther 31(2):199–200, 1982
Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE: Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50(4):219–244, 1966
Dorr RT, Alberts DS, Chen H-SG: The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse. Cancer Chemother Pharmacol 5:17–20, 1980
Dorr RT, Alberts DS, Stone A, Salmon SE: Cold protection from introdermal doxorubicin ulceration in the mouse. (Abstract) Proc Amer Assoc Cancer Res 24:255, 1983
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dorr, R.T., Peng, YM. & Alberts, D.S. Bisantrene solubility and skin toxicity studies: Efficacy of sodium bicarbonate as a local ulceration antidote. Invest New Drugs 2, 351–357 (1984). https://doi.org/10.1007/BF00171585
Issue Date:
DOI: https://doi.org/10.1007/BF00171585