Abstract
Interferon (IFN) and conventional cytotoxic chemotherapeutic agents have been successfully combined in various studies. Alpha difluoromethylornithine (DFMO) is a novel antitumor agent which is an inhibitor of polyamine metabolism. A phase I study of IFN 24 × 106 U/m2/day IM (days 3–7), DFMO 9 gm/m2 p.o. daily (days 1–7), and a variable dose of doxorubicin starting at 20 mg/m2 (day 6), of each 28 day cycle was performed. The aim of the study was to determine the maximally tolerable dose of doxorubicin in this combination. Three patients were treated with doxorubicin at 20 mg/m2 and six patients at 40 mg/m2. The dose limiting toxicities were neutropenia, fatigue and fever. All other toxicities were mild and there was no grade IV toxicity. A doxorubicin dose of 40 mg/m2 produced tolerable toxicity and is recommended for phase II studies. No major antitumor effects were seen.
Similar content being viewed by others
References
Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU: Alpha Interferon for induction of remission in hairy-cell leukemia. New Eng J of Med 310:15–18, 1984
Von Hoff DD:In vitro data supporting interferon plus cytotoxic agent combinations. Seminars in One 18:58–61, October 1991
Creagan ET, Frytak S, Long HJ, Kvols LK: Phase I study of Recombinant leukocyte A interferon (IFN-¶2A) with doxorubicin in advanced malignant disease. Cancer 64: 1034–1037, 1989
Green MD, Speyer JL, Hochster HS, Liebes LF, Dunleavy S, Widman T, Wernz JC, Blum RH, Spiegel RJ, Muggia FM: Phase I trial of escalating dose doxorubicin administered concurrently with ¶2-interferon. Cancer Research 48:2574–2578, 1988
Pegg AE, McCann PP: Polyamine metabolism & function. Am J Physiol 243:212–221, 1983
Mamont PS, Duchesne M, Grove J, Bey P: Anti-proliferative properties of DL-¶-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem Biophys Res Commun 81(l):58–66, 1978
Luk GD, Divin CI, Weissman RM, Baylin SB: Ornithine decarboxylase: essential in proliferation but not differentiation of human promyelocytic leukemia cells. Science 216:75–77, 1982
Luk GD, Goodwin G, Marton LJ, Baylin SB: Polyamines are necessary for the survival of human small-cell lung carcinoma in culture. Cell Biology 78:2355–2358, 1981
Kingsnorm AN, Russell WE, McCann PP, Diekema KA, Malt RA: Effects of ¶-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line. Cancer Research 43:4035–4038, 1983
Sunkara PS, Fowler SK, Nishioka K, Rao PN: Inhibition of polyamine biosynthesis by ¶-difluoromethyl ornithine potentiates the cytotoxic effects of arabinosyl cytosine in hela cells. Biochem Biophys Res Commun 95:423–430, 1980
Hung DT, Deen DF, Seidenfeld J, Marton JL: Sensitization of 9L rat brain gliosarcoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by ¶-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res 41: 2783–2785, 1981
Oredsson SM, Gray JW, Deen DF, Marton LJ: Decreased cytotoxicity of 1-β-D-arabinofuranosylcytosine in 9L rat brain tumor cells pretreated with ¶-difluoromethylornithinein vitro. Cancer Res 43:2541–2544, 1983
Edmonson JH, Kovach JS, Buckner JC, Kvols LK, Hahn RG: Phase I study of difluoromethylomithine in combination with recombinant ¶2a-interferon. Cancer Res 48: 6584–6586, 1988
Creagan ET, Long HJ, Ahmann DL, Schaid DJ: Phase II assessment of recombinant leukocyte A interferon with difluoromethylomithine in disseminated malignant melanoma. Am J Clin Oncol 13(3):218–220, 1990
Sunkara PS, Prakash NJ, Mayes GD, Sjoerdsma A: Tumor suppression with a combination of ¶-difluoromethyl ornithine and interferon. Science 219:851–853, 1983
Sarosy GA, Brown TD, Von Hoff DD, Spiegel RJ.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ganju, V., Edmonson, J.H. & Buckner, J.C. Phase I study of combined alpha Interferon, alpha difluoromethylornithine (DFMO), and doxorubicin in advanced malignancy. Invest New Drugs 12, 25–27 (1994). https://doi.org/10.1007/BF00873231
Issue Date:
DOI: https://doi.org/10.1007/BF00873231