Investigation of the interaction of cardiotoxic anticancer agents using the fetal mouse heart organ culture system.
The fetal mouse heart organ culture system was utilized in an effort to document and predict the potential cardiotoxic effects of ionizing radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ); alone and in combination. These antineoplastic agents have been shown to produce clinical cardiomyopathy which is often dose-limiting. Fetal mouse hearts (gestational day 17) were removed and placed in a culture system of 6-well microtiter plates. A single heart was placed in each well on a piece of aluminium mesh, above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment and incubated at 37 degrees C. Treatments performed on day 1 after culture were Cs-137 irradiation (10, 20, or 40 Gy); ADR (10, 30, or 100 micrograms/ml); DHAQ (5, 20, or 50 micrograms/ml); or various combinations of drugs and radiation. Hearts were checked every day for functional activity as evidenced by continuous heart best. Untreated hearts beat rhythmically for up to 9 days (average = 6.8 days); treated hearts stopped beating between 2 and 7 days after treatment. Using this endpoint of functional retention time (FRT), dose response curves were obtained for all individual agents. Combinations of ADR and DHAQ (at concentrations that resulted in FRTs of 3.5 days) produced no greater effect than either agent alone. However, the combination of radiation (FRT = 5.3 days) with ADR, DHAQ or both drugs was more effective than was drug alone. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000880:Anthraquinones / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D005720:Gamma Rays; D006321:Heart / Q000187:drug effects* / Q000196:embryology / Q000528:radiation effects; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D008942:Mitoxantrone; D009924:Organ Culture Techniques; D013997:Time Factors
D000880:Anthraquinones; D004317:Doxorubicin; D008942:Mitoxantrone