Phase I trial of mitoxantrone by 24-hour continuous infusion.

Mitoxantrone (DAD) is a new agent which intercalates into DNA. Preclinical studies have demonstrated activity equal to or greater than that of doxorubicin in all tumor systems tested. In this phase I clinical trial, the schedule of drug administration consisted of a 24-hour continuous iv infusion repeated at 21-day intervals. Twenty-nine patients received a total of 66 courses over a dose range of 4-15 mg/m2. The dose-limiting toxic effect was leukopenia, with a wbc count nadir on Day 12 and resolution prior to Day 21. Other toxic effects were thrombocytopenia, mild phlebitis, and blue discoloration of veins. Objective tumor responses were seen in a patient with adenocarcinoma of the breast and in another patient with clear cell carcinoma of the vagina. An additional six patients with acute leukemia were treated at a dose of 12 mg/m2; a decrease in peripheral blast count was observed in four of these six patients. The toxicity of DAD by 24-hour iv infusion was similar to that previously reported for iv bolus administration. We recommend phase II evaluation of DAD at a dose of 12 mg/m2 by single iv injection at 21-day intervals. Patients with acute leukemia should be evaluated at higher dose levels.

Adriamycin analogues. Preparation and biological evaluation of some novel 14-thiaadriamycins.

Condensation of 14-bromodaunorubicin with thiols in methanol, in the presence of potassium carbonate, resulted in the formation of 14-thia analogues of the antitumor antibiotic adriamycin. However, similar condensation of N-(trifluoroacetyl)-14-iododaunorubicin with thiols invariably led to a redox reaction, with the formation of N-(trifluoroacetyl)daunorubicin and disulfides. Accordingly, N-(trifluoroacetyl)-14-bromodaunorubicin was used for reaction with thiols to yield thia analogues of the clinically active but non-DNA-binding adriamycin analogue N-(trifluoroacetyl)adriamycin 14-valerate (AD 32). Reaction of 14-bromoadunorubicin with alpha, omega-alkanedithiols gave bis(thiaadriamycin) analogues as potential difunctional intercalating agents. The aforementioned products, plus two related phenylselena derivatives, were examined for in vitro growth inhibition, in vivo antitumor activity, and, where appropriate, DNA binding. A number of agents, most notably 14-(carbethoxymethyl)-14-thiaadriamycin and N-(trifluoroacetyl)-14-phenyl-14-selenaadriamycin, were active against murine L1210 leukemia in vivo. Several of the amino glycoside unsubstituted 14-thiaadriamycin analogues exhibited DNA-binding properties equivalent to those of adriamycin.

Pharmacologic studies with radiolabeled N-trifluoroacetyladriamycin-14-valerate (AD 32). Comparison of total anthracycline fluorescence and radioactivity in mouse serum and urine.

In connection with pharmacologic studies with AD 32, isotopically-labeled drug prepared from 1-[14C]-trifluoroacetic anhydride and adriamycin-14-valerate was used to determine murine serum and urine levels of radioactivity. Other studies, performed in parallel, measured serum and urinary total fluorescence. Serum fluorescence disappeared in a biphasic pattern, with an initial rapid rate of disappearance followed by a somewhat slower phase. For the first hour, serum radioactivity levels were not significantly different than those measured by fluorescence. After this, however, serum radioactivity decayed at a much slower rate than did fluorescence. Furthermore, a large fraction of the injected radioactivity was found excreted in the urine, whereas urine accounted for only a small fraction of the fluorescence. These results suggest the formation, in part, of a hitherto unrecognized nonfluorescent metabolite, most probably N-trifluoracetyldaunosamine.

Comparative metabolism and excretion of adriamycin in man, monkey, and rat.

Adriamycin and its fluorescent metabolites in bile (man, monkey, and rat) and urine (man and monkey) were determined by means of a simple, rapid, and highly reproducible high-performance liquid chromatographic procedure. Species differences in metabolism and biliary excretion were observed with respect to aldoketo reductase and conjugase activities.

Hepatobiliary metabolism and excretion of adriamycin and N-trifluoroacetyladriamycin-14-valerate in the rat.

In connection with mechanism of action studies with N-trifluoroacetlyadriamycin-14-valerate (AD 32), a superior Adriamycin (ADR) analog under development in these laboratories, serial bile samples were collected from male Sprague-Dawley rats given a single i.v. dose of either ADR (4 mg/kg) or AD 32 (20 mg/kg) and were analyzed for anthracyclines by thin-layer chromatography-fluorometry and high-performance liquid chromatography. For ADR, 20% of the administered dose was accounted for at 24 hr, whereas 80% of the AD 32 dose were excreted into the bile by this time. ADR underwent little biotransformation; 80% of the 48-hr cumulative fluorescence excretion was attributable to unchanged drug, one-half the remainder was adriamycinol, and the balance was polar conjugates. In contrast, AD 32 underwent extensive metabolism to N-trifluoracetyladriamycin, N-trifluoroacetyladriamycinol, and polar conjugates, mostly glucuronides of N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol. Based on direct and indirect evidence, ADR was not a metabolite of AD 32.