Cardiotoxicity of mitomycin A, mitomycin C, and sevenN 7 analogs in vitro

Abstract

The alkylating antitumor agents mitomycin A (MMA), mitomycin C (MMC), and seven N7 analogs were compared in terms of their cardiotoxic and antitumor activity in vitro. Neonatal rat-heart myocytes were sensitive to five of the compounds studied, including MMA, 7-dimethylamidinomitosane (BMY-25282), 7-(N-methyl-piperazinyl)-mitosane (RR-194), N7-(4-iodophenyl)-MMC (RR-208), and N7-(4-hydroxyphenyl)-MMC (M-83) in order of descending molar potency. MMA and RR-208 possessed the greatest cytotoxic potency against 8226 human myeloma tumor cells in vitro. Two of the nine mitomycins studied, BMY-25282 and M-83, showed greater cytotoxic potency for heart cells. For these two agents, the ratio of the 50% inhibitory concentration in heart cells to that in 8226 myeloma cells was 50 and 32, respectively. For the other analogs, the tumor-cell cytotoxic potency was much higher (ranging from 200 to 7,000). For the nine mitomycin compounds, a correlation was found between heart-cell toxicity and low reduction potentials (E1/2 values) ranging from -0.16 to -0.37 V. Thus, as the reduction potential decreased (easier reducibility), the cardiotoxic potency in vitro increased (r = 0.81). In contrast, mitomycins with reduction potentials of higher than -0.37 V were much less potent cardiotoxins. Thus, mitomycin C (E1/2 = -0.45 V) was noncardiotoxic even when tested at concentrations 100-fold above those pharmacologically achievable in humans. Mitomycin C also failed to enhance doxorubicin (Adriamycin) cardiotoxicity in vitro. Importantly, no correlation was found between the reduction potential and the antitumor activity of the nine analogs (n = 0.51), in this small series.

Selective Activation of Mitomycin A by Thiols To Form DNA Cross-links and Monoadducts: Biochemical Basis for the Modulation of Mitomycin Cytotoxicity by the Quinone Redox Potential

“…Typically, MA derivatives were 2 orders of magnitude more potent than the corresponding MC derivatives . Furthermore, a significant correlation was observed between in vitro cardiotoxicity and redox potential, MA being 3 orders of magnitude more cardiotoxic than MC to rat heart cells …”

“…Mitomycin A (MA; 1b ), which differs from MC only in its 7-substituted group (7-methoxy instead of 7-amino), exhibited high toxicity in experimental animals, which prevented its clinical use. Furthermore, MA is several orders of magnitude more cytotoxic to tumor cells than MC. , Extensive SAR studies established that mitomycins with 7-alkoxy substituents had higher redox potentials than 7-nitrogen-substituted mitomycins (e.g., E 1/2 of MA and MC are −0.19 and −0.40 V, respectively) and that a strong correlation existed between E 1/2 and the activity of these mitomycins. ,

1

…”

“…Furthermore, MA is several orders of magnitude more cytotoxic to tumor cells than MC. 6,7 Extensive SAR studies established that mitomycins with 7-alkoxy substituents had higher redox potentials than 7-nitrogen-substituted mitomycins (e.g., E 1/2 of MA and MC are -0.19 and -0.40 V, respectively) and that a strong correlation existed between E 1/2 and the activity of these mitomycins. 8,9 Reductive activation of MC as prodrug is catalyzed by several different flavoreductases in mammalian cells.…”

Phase I study of the mitomycin C analogue BMS-181174

“…Haemolytic-uraemic syndrome can occur and is particularly likely in patients who receive a cumulative dose of over 60 mg (Martino et al, 1979;Ratanatharathom et al, 1979;Rabadi et al, 1982). Preclinical studies have shown that BMS-181174 is cardiotoxic in rats, although not in mice or dogs (Dorr et al, 1992). In our phase I study we saw some evidence of impairment of cardiac function as measured by changes in LVEF.…”

“…There have also been reports of pulmonary fibrosis, nephrotoxicity and haemolytic-uraemic syndrome (Carter and Crooke, 1979;Rabadi et al, 1982). MMC is cardiotoxic in animals and in patients when given with or after doxorubicin (Dorr et al, 1992). The clinical use of MMC is limited by these toxicities and by the emergence of drug resistance.…”