Characterization of the toxicity of distamycin derivatives on cancer cell lines and rat heart.
The cytotoxicity and cardiotoxicity of benzoyl mustard (FCE 24517) and epoxamido (FCE 24561) synthetic derivatives of distamycin A were reported in the present study. The 50% inhibiting concentration (IC50) of colony formation of FCE 24517 on human SNB-19 glioblastoma, A2780 ovarian cancer and DU 145 prostate cancer was at least three times lower than that of FCE 24561; on the same cell lines the IC50 of DXR was up to 14 and 240 times higher than that of FCE 24561 and FCE 24517, respectively. Isolated rat hearts perfused with concentrations of both derivatives equivalent to their respective IC50 values did not show any significant change in ECG parameters, contractility and coronary flow. Compared to control hearts, FCE 24517 10(-6) M induced a significant increase in PR interval, reduction in + dF/dtmax, heart rate and coronary flow, while FCE 24561 10(-6) M produced a modest but significant increase in S alpha T segment and decrease in + dF/dtmax. Rats treated with FCE 24561 3, 6 or 12 mg/kg, intravenously (i.v.), once weekly for 3 weeks had a modest increase in S alpha T segment and QRS complex duration, while a slight alteration of S alpha T segment and QRS complex duration were observed in rats given FCE 24517 1 or 2 mg/kg i.v. once weekly for 3 weeks. No cardiac histologic alterations were found in hearts from rats receiving FCE 24517 or FCE 24561. For comparison, the cardiotoxicity of doxorubicin (DXR) was evaluated in the same experimental models; perfusion of hearts with DXR 10(-6) M induced severe alterations in all parameters of the isolated hearts; the administration of DXR 3 mg/kg i.v. once a week for 3 weeks was associated with a widening of the S alpha T segment and QRS complex and cardiac histologic picture was markedly altered. In conclusion, distamycin A derivatives display elevated cytotoxicity while no substantial cardiotoxicity was observed.
Agen
C
C
Institute of Medical Pharmacology, University of Pisa, Italy.
Sironi
A M
AM
Danesi
R
R
Costa
M
M
Bernardini
N
N
Paparelli
A
A
Della Torre
P
P
Del Tacca
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004214:Distamycins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C078526:FCE 24561; C066900:tallimustine; D004317:Doxorubicin