Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro

Robert T Dorr, Nancy G. Shipp, James D. Liddil, Bhashyam S. Iyengar, Kenneth R. Kunz, William A. Remers

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-5
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume31
Issue number1
DOIs
StatePublished - Jan 1992

Fingerprint

Mitomycin
Mitomycins
Doxorubicin
Tumors
Cardiotoxins
Alkylating Agents
Antineoplastic Agents
Muscle Cells
Inhibitory Concentration 50
Toxicity
Cardiotoxicity
In Vitro Techniques
mitomycin A
Rats
Neoplasms
Cells

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro. / Dorr, Robert T; Shipp, Nancy G.; Liddil, James D.; Iyengar, Bhashyam S.; Kunz, Kenneth R.; Remers, William A.

In: Cancer Chemotherapy and Pharmacology, Vol. 31, No. 1, 01.1992, p. 1-5.

Research output: Contribution to journalArticle

Dorr, Robert T ; Shipp, Nancy G. ; Liddil, James D. ; Iyengar, Bhashyam S. ; Kunz, Kenneth R. ; Remers, William A. / Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro. In: Cancer Chemotherapy and Pharmacology. 1992 ; Vol. 31, No. 1. pp. 1-5.
@article{347656ac9ad646eb854ae77356653f06,
title = "Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 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.",
author = "Dorr, {Robert T} and Shipp, {Nancy G.} and Liddil, {James D.} and Iyengar, {Bhashyam S.} and Kunz, {Kenneth R.} and Remers, {William A.}",
year = "1992",
month = "1",
doi = "10.1007/BF00695986",
language = "English (US)",
volume = "31",
pages = "1--5",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro

AU - Dorr, Robert T

AU - Shipp, Nancy G.

AU - Liddil, James D.

AU - Iyengar, Bhashyam S.

AU - Kunz, Kenneth R.

AU - Remers, William A.

PY - 1992/1

Y1 - 1992/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0026463647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026463647&partnerID=8YFLogxK

U2 - 10.1007/BF00695986

DO - 10.1007/BF00695986

M3 - Article

VL - 31

SP - 1

EP - 5

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -