Antitumor activity of mitoxantrone against murine experimental tumors: Comparative analysis against various antitumor antibiotics

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Abstract
Summary 1,4-Dihydroxy-5,8-bis{{{{2-[(2-hydroxyethyl)amino]ethyl}amino}}-9,10-anthracenedione dihydrochloride (mitoxantrone) was tested for antitumor activity against experimental tumors in mice and the results were compared with those of seven antitumor antibiotics: adriamycin (ADM), daunomycin (DM), aclarubicin, mitomycin C (MMC), bleomycin, neocarzinostatin, and chromomycin A3. The drugs were given IP or IV, in general on days 1,5, and 9 following tumor inoculation. Mitoxantrone given IP at the optimal dose (1.6 mg/kg/day; as a free base) produced a statistically significant number of 60-day survivors (curative effect) in mice with IP implanted L1210 leukemia. The curative effect was not observed with any of the other antibiotics. In the case of IV implanted L1210 leukemia, there was an increase in lifespan (ILS) by more than 100% in the mice following IV treatment with mitoxantrone or DM. In IP implanted P388 leukemia, the curative effect was elicited by IP treatment with mitoxantrone or MMC. In IP implanted B16 melanoma, both the curative effect and a more than 100% ILS in mice that did die were produced by IP treatment with mitoxantrone or ADM. In SC implanted Lewis lung carcinoma, mitoxantrone and ADM administered IV also showed effective antitumor activities and produced a 60% and a 45% ILS, respectively. In conclusion, mitoxantrone and ADM had a wider spectrum of antitumor activity against mouse tumors, including two leukemias and two solid tumors, than did the other drugs; however, mitoxantrone elicited higher antitumor effects than ADM on mouse leukemias, especially on L1210 leukemias. Moreover, mitoxantrone possessed much higher therapeutic indices than ADM against IP implanted P388 (optimal dose/ILS40; >128 versus 15.2) and L1210 (optimal dose/ILS25; 72.7 versus 4.8) leukemias. In addition, mitoxantrone showed moderate activity against DM-resistant L1210 leukemia.