Summary
A phase II trial of menadione [2.5 gm/m2 as a continuous intravenous (iv) infusion over 48 hours] followed by mitomycin C (10–20 mg/m2 iv bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60–90%. Two of the 23 patients (9%; 95% confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up response data to estimate response duration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade 3 or 4 hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease in left ventricular ejection fraction: one patient remained asymptomatic, but the other patient developed congestive heart failure. Although only 9% of patients had confirmed objective responses, 28% (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regressions fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.
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References
Dorr RT: New findings in the pharmacokinetic, metabolic, and drug-resistance aspects of mitomycin C. Semin Oncol 15:32–41, 1988
Doroshow JH: Role of hydrogen peroxide and hydroxyl radical formation in the killing of Erlich tumor cells by anticancer quinones. Proc Natl Acad Sci U.S.A. 83:4514–4518, 1986
Dusre L, Rajagopalan S, Eliot HM, Covey JM, Sinha BK: DNA interstrand cross-link and free radical formation in a human multidrug — resistant cell line from mitomycin C and its analogues. Cancer Res 50:648–652, 1990
Pritsos CA, Sartorelli AC: Generation of reactive oxygen radicals through bioactivation of mitomycin C antibiotics. Cancer Res 46:3528–3532, 1986
Akman SA, Doroshow JH, Dietrich MF, Chlebowski RT, Block JS: Synergistic cytotoxicity between menadione and dicumarolvs. murine leukemia L1210. J Pharmacol and Exp Ther 240:486–491, 1987
Chlebowski RT, Akman SA, Block JB: Vitamin K in the treatment of cancer. Cancer Treat Rev 12:49–63, 1985
Su Y-Z, Duarte TE, Dill PL, Weisenthal LM: Selective enhancement by menadiol ofin vitro drug activity in human lymphatic neoplasms. Cancer Treat Rep 71:619, 1987
Akman S, Carr B, Leong L, Margolin K, Odujinrin O, Doroshow J: Phase I trial of menadiol sodium diphosphate (SYNKAYVITE ®) (M) in advanced cancer. Proc Am Soc Clin Oncol 7:76, 1988
Doroshow JH, Burke T: Resistance to anticancer quinone-induced cytotoxicity produced by introduction of glutathione-S-transferase (GST) into human MCF-7 breast cancer cells. Proc Amer Assoc Cancer Res 29:271, 1988
Margolin K, Akman S, Doroshow J, Leong L, Morgan R, Raschko J, Somlo G, Flanagan B: Modulation of alkylator resistance by 2-methyl-1,4-naphthoquinone (menadione): Phase I trials of combination menadione plus cyclophosphamide or mitomycin C. Proc Am Soc Clin Oncol 9:83, 1990
Kris M: Mitomycin in combination chemotherapy regimens for patients with advanced non-small cell lung cancer. In: Gralla R, Einhorn L (eds).Treatment and prevention of small cell lung cancer and non-small cell lung cancer. London: Royal Society of Medicine Services, pp. 101–108, 1989
Lesesne JB, Rothschild N, Erickson B: Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry. J Clin Oncol 7:781–789, 1989
Doroshow JH, Leong L, Margolin K, Flanagan B, Goldberg D, Bertrand M, Akman S, Carr B, Odujinrin O, Newman E, Litchfield T: Refractory metastatic breast cancer: salvage therapy with fluorouracil and high-dose continuous infusion leucovorin calcium. J Clin Oncol 7:439–444, 1989
Kaplan ER, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958
Verweij J, Funke-Kupper AJ, Teule GJJ, Pinedo HM: A prospective study on the dose dependency of cardiotoxicity induced by mitomycin C. Med Oncol Tumor Pharmacother 5:159–163, 1988
Savarese DMF, Denicoff AM, Berg SL, Hillg M, Baker SP, O'Shaughnessy JA, Chow C, Otterson GA, Balis FM, Poplack DG, Cowan KH: Phase I study of high-dose piroxantrone with granulocyte colony-stimulating factor. J Clin Oncol 11:1795–1803, 1993
Ingle JN, Kuross SA, Mailliard JA, Loprinzi CL, Jung S, Nelimark RA, Krook JE, Long HJ: Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy. Cancer 74:1733–1738, 1994
Keizer HG, De Leeuw SJ, Van Rijn J, Pinedo HM, Joenje H: Effect of electron acceptors on the cytotoxicity of mitomycin C and doxorubicin in human lung tumor cells. Eur J Cancer Clin Oncol 25:1113–1118, 1989
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Tetef, M., Margolin, K., Ahn, C. et al. Mitomycin C and menadione for the treatment of lung cancer: a phase II trial. Invest New Drugs 13, 157–162 (1995). https://doi.org/10.1007/BF00872865
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DOI: https://doi.org/10.1007/BF00872865