Summary
FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3–4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.
Similar content being viewed by others
References
Verweij J, den Hartigh J, Pinedo HM: Antitumor antibiotics. In: Chabner BA, Collin J (eds) Cancer Chemotherapy: Principles and Practice. J.B. Lippincottt, Philadelphia, 1990, pp. 382–396
Uchida I, Takase S, Kayakiri H, Kiyoto S, Hashimoto M: Structure of FR 900482, a novel antitumor antibiotic from a Streptomyces. Journal of the American Chemical Society 109:4108–4109, 1987
Fujita T, Takase S, Otsuka T, Terano H, Kohsaka M: Precursors in the biosynthesis of FR-900482, a novel antitumor antibiotic produced by Streptomyces sandaensis. J Antibiot (Tokyo) XLI:392–394, 1988
Iwami M, Kiyoto S, Terano H, Kohsaka M, Aoki H, Imanaka, H: A new tumor antibiotic, FR-900482. Taxonomic studies on the producing strain. A new species of Streptomyces. J Antibiot (Tokyo) XL:589–593, 1987
Kiyoto S, Shibata T, Yamashita M, Komori T, Okuhara M, Terano H, Kohsaka M, Aoki H, Imanka H: A new antitumor antibiotic, FR-900482. Production, isolation, characterization and biologic activity. J Antibiot (Tokyo) XL:594–599, 1987
Shimomura K, Hirai O, Mizota T, Matsumoto S, Mori J, Shibayama F, Kikuchi H: A new tumor antibiotic, FR-900482. Antitumor activity in transplantable experimental tumors. J Antibiot (Tokyo) XL:600–606, 1987
Hirai O, Shimomura K, Mizota T, Matsumoto S, Mori J, Kikuchi H: A new antitumor antibiotic, FR-900482. Hematological toxicity in mice. J Antibiot (Tokyo) XL:607–611, 1987
Shimomura K, Manda T, Mukumoto S, Masuda K, Nakamura T, Mizota T, Matsumoto S, Nishigaki F, Oku T, Mori J, Shibayama F: Antitumor activity and hematotoxicity of a new, substituted dihydrobenzoxazine, FK973, in mice. Cancer Res 48:1166–1172, 1988
Horiuchi N, Nakagawa K, Sasaki Y, Fujiwara Y, Nezu K, Obe Y, Saijo N: In vitro antitumor activity fo mitomycin C derivative (RM-49) and new anticancer antibiotic (FK973) against lung cancer cell lines determined by tetrazolium dye (MTT) assay. Cancer Chemother Pharmacol 22:246–250, 1988
Nakamura T, Masuda K, Matsumoto S, Manda T, Mori J, Shimomura K: Effect of FK973, a new antitumor antibiotic, on the cell cycle of L1210 cells in vitro. Jpn J Pharmacol 49:317–324, 1989
Masuda K, Nakamura T, Mizota T, Shimomura K: Interstrand DNA-DNA and DNA-protein cross-links by a new antitumor antibiotic, FK973, in L1210 cells. Cancer Res 48:5172–5177, 1988
Aggarwal BB, Kohr WJ, Hass PE, Moffat B, Spencer SA, Henzel Q, Bringman TS, Nedwin GE, Goeddel DB, Harkins, RN: Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem 260:2345–2354, 1985
Siegel JP, Puri RK: Interleukin-2 toxicity. J Clin Oncol 9:694–704, 1991
Brandt SJ, Peters WP, Atwater SK: Effect of human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 318:869–876, 1988
Rosenstein M, Ettinghausen SE, Rosenberg SA: Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2. J Immunol 137L:1735–1742, 1986
Fairman RP, Glauser FL, Merchant RE: Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2. Cancer Res 47:3528–3532, 1987
Ettinghausen SE, Puri RK, Rosenberg SA: Increased vascular permeability in organs mediated by the systemic administration of lymphokine-activated killer cells and recombinant interleukin-2 in mice. J Natl Cancer Inst 80:177–188, 1988
Sobel AT, Branellec AI, Blanc GJ: Physiochemical characterization of a vascular permeability factor produced by Con-A-stimulated human lymphocytes. J Immunol 119:1230–1234, 1977
Horvath CJ, Ferro TJ, Jesmok G: Recombinant tumor necrosis factor increases pulmonary vascular permeability independent of neutrophils. Proc Natl Acad Sci USA 85:9219–9223, 1988
Buzdar AU, Legha SS, Tashima CK, Hortobagyi GN, Yap HY, Krutchik AN, Luna MA, Blumenschein GR: Adriamycin and mitomycin C. Possible synergistic cardiotoxicity. Cancer Treatment Reports 62:1005–1008, 1978
Author information
Authors and Affiliations
Additional information
Address for offprints: R. Pazdur, Division of Medicine, Box 92, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
Rights and permissions
About this article
Cite this article
Pazdur, R., Ho, D.H., Daugherty, K. et al. Phase I trial of FK973: Description of a delayed vascular leak syndrome. Invest New Drugs 9, 377–382 (1991). https://doi.org/10.1007/BF00183587
Issue Date:
DOI: https://doi.org/10.1007/BF00183587