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Two sublines of the ovarian reticular cell sarcoma M5 in C57BL mice respond differently to cyclophosphamide and other alkylating agents. The subline R16, which is resistant to cyclophosphamide, was obtained by treating M5 mice repeatedly with this compound and subsequently transplanting the regrowing tumor for 16 passages. The R16 subline shows biological characteristics perfectly superimposable to those of the parent line and histologically resembles an undifferentiated mesenchymal neoplasia with numerous atypical nuclei and karyokinetic figures with large necrotic areas. The cytogenetic examination of the distribution in the chromosomal number of R16 indicates that this subline may be considered a clone of the parent line with a modal class of 35 chromosomes (34–37) versus a class of 34 (31–37) in the M5 tumor line. The presence of metacentric chromosomes characterizes the modal class of the two lines, 23 in the R16, and 25 in the M5 tumor lines.

VP16 and VM26 were determined by high pressure liquid chromatography in intracerebral tumors, adjacent normal brain tissue, plasma and CSF samples from 24 patients given the two drugs before surgical resection of the tumor. The drugs were administered at doses of 100-150 mg/m2 as a 1-hour i.v. infusion, between 1.5 and 12 hours before surgery. Concentrations of VP16 ranged between 1.05 and 3.28 micrograms/g in tumors in the series of patients who received the drug 1.5-3 hours before surgery and between less than 0.05 and 1.12 micrograms/g in four patients who received the drug 9-13 hours before surgery. Tumor concentrations of VM26 also varied, ranging from less than 0.05 to 1.68 micrograms/g between 1.5 and 12 hours before surgery. VP16 and VM26 in the apparently normal brain tissue surrounding the tumor were low or undetectable except in one patient who had received radiotherapy, in whom we found 3.1 micrograms/g.

The acute cardiac toxicity of three second-generation anthracycline analogues and doxorubicin was compared in a model of the rat isolated Langendorff perfused heart. The drugs, doxorubicin (DX), 4-epi-doxorubicin (4′EDX), 4-demethoxy-daunorubicin (4DMDR) and 4′-deoxy-doxorubicin (4′dxDX) were infused for 40 min at a concentration of 26 μM into the isolated hearts. All four compounds significantly reduced cardiac work and its first derivative. The time to 50% decrease in work (TW50) was respectively 36, 23, 9 and 7 min for DX, 4′EDX, 4′dxDx and 4DMDR. The three anthracycline derivatives, but not DX, significantly increased coronary resistance. Heart rate was reduced by all compounds compared with baseline, but not compared with controls. Rhythm disturbances were seen with all five hearts perfused with 4DMDR, which stopped beating before 40 min; 2/5 hearts in the 4′EDX group and 1/5 hearts in the 4′dxDX group also stopped before the end of perfusion. All the compounds reached concentrations in the myocardium 8 to 50 times higher than in the perfusing medium. The more cardiotoxic the compound, the higher was its myocardial concentration; a significant correlation was found for all four agents. Noradrenaline was never measurable in the perfusate of control and DX hearts; perfusion with the three anthracycline derivatives caused some release, but the pattern was not clearcut and the maximum concentrations attained in the perfusate were relatively low (< 1ṁ6 times 10−9 M). In conclusion, in the rat isolated perfused heart, the early cardiotoxicity induced by equimolar concentrations of the three anthracycline compounds was greater than that induced by DX and was directly related to drug accumulation in the myocardium. Catecholamines do not seem to have a major role in the development of toxicity in this model.