Summary
Bleomycin is an agent with significant antitumor efficacy whose major dose limiting toxicity is pulmonary fibrosis. Attempts have thus been made to identify congeners with reduced toxicity and with comparable or greater antitumor activity. Tallysomycin S10b is a bleomycin analogue possessing significantly greater potency, equal or reduced lung toxicity, and slightly greater antineoplastic activity when compared to the parent compound in preclinical studies. This report describes our experience with tallysomycin S10b in 30 patients with a variety of non-hematologic neoplasms. Pulmonary toxicity, occurring in 4 patients, was the major toxicity. The recommended cumulative dose of tallysomycin S10b was difficult to establish from the results of this study, as pulmonary toxicity appeared to be more idiosyncratic than dose-or schedule-dependent. The employment of more sensitive methods for detecting pulmonary toxicity in this study suggest that tallysomycin S10b may have reduced pulmonary toxicity compared to the parent compound.
Both bleomycin and tallysomycin S10b have similar t1/2 βhalf-lives of 2–4 h. Six patients had prolonged terminal elimination half-lives of tallysomycin S10b, but no clear relationship between this phenomenon and efficacy or toxicity was evident.
No complete or partial responses occurred. Disease stabilization occurred in 4 of 15 patients with diagnoses of renal cell carcinoma [2], rectal cancer [1] and lung cancer [1]. Five of eight patients with non-measurable disease had stable disease, including one with mesothelioma, one with carcinoma of the head and neck, two with renal cell cancer and one with colon carcinoma.
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References
Umezawa H, Meada K, Takeuchi I, Toshioka O: New antibiotics bleomycin A and B. J Antibiot A (Tokyo)19:200–206, 1966
Rodriguez V, Cabanillas F, Burgess MA, McKelvey E, Valdivieso M, Bodey G, Freireich EJ: Combination chemotherapy (“CHOP-bleo”) in advanced non-Hodgkin's malignant lymphoma. Blood49:325–333, 1977
Schein PS, DeVita VT, Hubbard S, Chabner BA, Canellos GP, Berard C, Young RC: Bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma. Ann Int Med 85:417–422, 1976
Krikorian JG, Portlock CS, Rosenberg SA: Treatment of advanced Hodgkin's disease with adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) after failure of MOPP therapy. Cancer 41:2107–2111, 1978
Kilmo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large cell lymphoma. Ann Int Med 102:596–602, 1985
Anderson KC, Skarin AT, Rosenthal DS, McIntyre JM, Pinkus GS, Case DC, Leonard RCF, Canellos GP: Combination chemotherapy for advanced non-hodgkin's lymphomas other than diffuse histiocytic or undifferentiated histologies. Cancer Treat Rep 68:1343–1350, 1984
Santoro A, Bonfante V, Bonadonna G: Salvage chemotherapy with ABVD in MOPP-resistant Hodgkin's disease. Ann Int Med 96:139–143, 1982
Bleier K: Relations between histology, TNM-category and results of treatment with methotrexate-bleomycin combination in squamous cell carcinoma of the oral cavity. J Maxillofac Surg 1:113–117, 1973
Einhorn LH, Donohue J: Cis-diamminedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Int Med 87:293–298, 1977
Ginsberg SJ, Comis RL: The pulmonary toxicity of antineoplastic agents. Semin Oncol 9:34–51, 1982
Crooke ST, Einhorn LH, Comis RL, D'Aoust JC, Prestayko AW: The effects of prior exposure to bleomycin on the incidence of pulmonary toxicities. Med Pediatr Oncol 5:93–98, 1978
Samuels ML, Johnson DE, Holoye PY, Lanzotti VJ: Large dose bleomycin pulmonary toxicity. A possible role of prior radiotherapy. JAMA 235:1117–1120, 1976
Einhorn LH, Krause M, Hornback N, Furnas B: Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 37:2414–2426, 1976
Skarin A, Lokich J, Goodman R: Combined intensive chemotherapy and radiotherapy in oat cell carcinoma of the lung. Proc Amer Soc Clin Oncol 16:264, 1975
Goldiner PL, Carlon GC, Cvitkovic E, Schweize O, Howland WS: Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1:1664–1677, 1978
Blum RH, Carter SK, Agre K: A clinical review of bleomycin. A new antineoplstic agent. Cancer 31:903–914, 1973
Hoogstraten B, Hass CD, Haut A, Talley RW, Rivkin S, Isaacs BL: CCNU and bleomycin in the treatment of cancer. A Southwest Oncology Group study. Med Pedatr Oncol 1:95–106, 1975
Miyaki T, Numata K, Nishiyama Y, Tenmyo O, Hatari M, Imanishi H, Konishi M, Kawaguchi H: Tallysomycin, a new antitumor antibiotic complex related to bleomycin. V. Production, characterization and antitumor activity to Tallysomycin S10b, a new biosynthetic tallysomycin derivative. J Antibiot (Tokyo) 34:665, 1981
Imanishi H, Ohbayashi M, Nishiyama Y, Kawaguchi H: Tallysomycin, a new antitumor antibiotic complex related to bleomycin. III. Antitumor activity of tallysomycins A and B. J Antibiot (Tokyo) 31:667–673, 1978
Schurig JE, Rose WC, Hirth RS, Schlein A, Huftalen JB, FLorczyk AP, Bradner WT: Tallysomycin S10b: Experimental antitumor activity and toxicity. Cancer Chemother Pharmacol 13:164–170, 1984
DeVita Vt, Hellman S, Rosenberg SA, eds. Cancer, Principles and Practice of Oncology 2nd Ed. Philadelphia. Lippincott; 1982, p. 536.
Gaver RC, Dixon CW, Smyth RD: A radioimmunoassay procedure for tallysomycin S10b in human plasma and urine. Cancer Chemother Pharmacol 16(3):207–210, 1986
Gibaldi M, Perrier D: Pharmacokinetics. 2nd ed. Marcel Dekker, Inc. New York. 1982
Riegelman S, Collier P: The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J Pharmacokin Biopharm 8:509–534, 1980
Snedecor GW, Cochran WG: Statistical Methods. 7th Ed. Iowa State University Press. Ames Iowa, 1980, pp 149–174
Miller AB, Hoogstraten B, Staguet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207–214, 1981
DeLena M, Guzzon A, Monfardini S, Bonnadonna G: Clinical, radiological and histopathological studies on pulmonary toxicity induced by treatment with bleomycin (NSC 125066). Cancer Chemother Rep 56:343–356, 1972
Alberts DS, Chen H, Liu R, Himmelstein KJ, Mayerson M, Perrier D, Gross J, Moon T, Broughton A, Salmon SE: Bleomycin pharmacokinetics in man. I. Intravenous administration. Cancer Chemother Pharmacol 1:177–181, 1978
Hall SW, Strong JE, Broughton A, Frazier ML, Benjamin RS: Bleomycin clinical pharmacology by radioimmunoassay. Cancer Chemother Pharmacol 9:22–25, 1982
Crooke ST, Comis RL, Einhorn L, Strong JE, Broughton A, Prestayko AW: Effects of variations in renal function on the clinical pharmacology of bleomycin administered as an IV Bolus. Cancer Treat Rep 61(9):1631–1636, 1977
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Paolozzi, F.P., Gaver, R.C., Newman, N.B. et al. Phase I trial of tallysomycin S10b, a bleomycin analogue. Invest New Drugs 8, 171–180 (1990). https://doi.org/10.1007/BF00177253
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DOI: https://doi.org/10.1007/BF00177253