Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro.
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.
Dorr
R T
RT
College of Medicine, University of Arizona, Tucson.
Shipp
N G
NG
Liddil
J D
JD
Iyengar
B S
BS
Kunz
K R
KR
Remers
W A
WA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity; D003864:Depression, Chemical; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006331:Heart Diseases / Q000139:chemically induced*; D008297:Male; D016685:Mitomycin / Q000633:toxicity*; D008937:Mitomycins / Q000633:toxicity*; D009101:Multiple Myeloma / Q000188:drug therapy; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects
D008937:Mitomycins; D011506:Proteins; D016685:Mitomycin; D004317:Doxorubicin; C046000:mitomycin A; D000255:Adenosine Triphosphate