Eighteen patients with advanced malignancies refractory to other forms of treatment were given dactinomycin (Act D) as continuous intravenous infusions. Their median age was 51 years (range, 36-67); their median performance status was 50 (range, 40-90) on the Karnofsky scale. Act D was administered continuously for 5 days, utilizing a central venous line and a perfusion pump. The starting dose was 0.1 mg/m2/24 hours X 5 days (total dose, 0.5 mg/m2) and was escalated according to a modified Fibonacci scale to 0.2, 0.33, and 0.5 mg/m2/24 hours X 5 days, respectively. Three, three, four, and eight patients were entered, respectively, in each dose level. Toxicities observed were: leukopenia in four patients (nadir leukocyte count 4 0 0 0 cells/mm3 in one patient and 2000-3000 cells/mm3 in 3 patients); thrombocytopenia, with nadir platelet counts between 50,OOO and 100,OOO platelets/mm3 in 2 patients; stomatitis in four patients; and nausea in three patients. Vomiting was not observed during the infusions. Two patients may have had a radiation recall phenomenon. Blood count depression, nausea, and mucositis were transient, resolving after a few days. One patient at level IV died of sepsis, which was diagnosed on the fourth day of the infusion, before leukopenia intervened. No objective responses were seen. It was concluded that a higher dose of Act D can be given by continuous infusion than by a bolus injection; the authors recommended 0.5 mg/m2/day X 5 days (total dose, 2.5 mg/m2) for further studies.
Cancer 56:256-258, 1985. HE ACTINOMYCINS are antibiotics synthesized by T Stepfomyces species. Dactinomycin (Act D) is used clinically. It is active in gestational and germ cell tumors, Wilms' tumor, and some sarcomas. Structurally, they have a phenoxazone ring, which intercalates with DNA, and two cyclic pentapeptides, which extend into the minor groove of the helix.
At low doses, DNA-dependent RNA synthesis is impaired, whereas at higher doses DNA and protein synthesis are affected.' After a bolus intravenous injection, Act D is cleared from the plasma within minutes,