Alain Gouyette

Phase I and pharmacological study of intra-arterial hepatic administration of pirarubicin in patients with advanced hepatic metastases

Intra-arterial hepatic (i.a.h.) administration of the doxorubicin analogue pirarubicin was evaluated in a phase I trial, based on preclinical studies that showed an advantage of pirarubicin over doxorubicin after locoregional hepatic administration. Pirarubicin was given to 9 patients with metastatic liver disease with intrapatient dose escalation. Of the 58 cycles evaluable for tolerance, no hepatobiliary or vascular toxicity was observed. The dose-limiting toxicity was granulocytopenia: the maximum administered doses ranged from 50 to 120 mg/m2, suggesting variable rates of pirarubicin hepatic extraction between patients. Pharmacokinetic data obtained in 7 patients, in which a direct comparison of intravenous (i.v.) and i.a.h. administration was possible, indicated a median i.v./i.a.h. ratio of 7.4 for the maximal plasma concentration, and a median ratio of 4 for the area under the plasma concentrations versus time curves, suggesting a high pirarubicin hepatic extraction. An unexpectedly high response rate was observed: two complete (colorectal carcinoma) and two partial responses. These data demonstrate that i.a.h. pirarubicin not only produced high locoregional concentrations and reduced systemic exposure, but can also achieve responses in metastatic liver disease of colorectal origin.

Effect on L1210 Leukemia, on Antibody Forming Cells, and on Macrophage Cytotoxicity of Ellipticine and 3 Derivatives

In 1970 Mathe et al. (8) published the oncostatic effect of 9-methoxy-ellipticine (lactate) extracted from Ochrosia bcrbpnica, on human acute otyeloid leukaemia. Garcia-Giralt and Macieira- Coelho (4) showed that this agent, active on murine tumors (11,14), inhibits DNA synthesis strongly. But they observed that it also blocks noticeably RNA and protein synthesis, which probably explains why it is not a cycle dependant agent.