chartreusin and Breast-Neoplasms

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC_0-24h=C_8hx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Area Under Curve; Benzopyrans; Breast Neoplasms; Drug Monitoring; Female; Glycosides; Humans; Middle Aged; Tissue Distribution

The in vitro activity of elsamicin A (ELS) was investigated compared with that of doxorubicin (DX) on two sensitive breast cancer cell lines: one estrogen receptor-positive (ER+, MCF7) and one estrogen receptor-negative (ER-, MDA-MB-231) line, and on a DX-resistant subline (MCF7DX). The activity of the two drugs was also investigated on 19 clinical breast cancer specimens from untreated patients. The drugs were tested at pharamcologically relevant concentrations, as calculated from the area under the curve for a 3 h exposure to the lethal dose producing 10% mortality (LD10) in mice, and at 10- and 100-fold concentrations. In DX-sensitive lines, a greater inhibition of RNA and DNA precursor incorporation, as well as of cell proliferation, was caused by ELS than by DX. Moreover, the antiproliferative effect was 10-fold higher in the ER+ MCF7 than in the ER- MDA-MB-231 cell line (IC50: 0.25 versus 0.21 micrograms/ml). ELS was cross-resistant to DX in the MCF7DX subline. In clinical specimens, effects on DNA precursor incorporation were more often observed for ELS than for DX at the same drug concentrations. The in vitro sensitivity to ELS was more pronounced for ER+ than for ER- tumors: minimal inhibiting concentrations of the drug were 0.1 and 3.5 micrograms/ml, respectively, in the two groups. If confirmed in a larger series of human breast tumors, these in vitro results would indicate a promising role for ELS in clinical treatment, mainly of ER+ breast cancer patients.

Topics: Adenocarcinoma; Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Benzopyrans; Breast Neoplasms; Cell Division; DNA, Neoplasm; Doxorubicin; Drug Resistance; Female; Glycosides; Humans; Mice; Receptors, Estrogen; RNA, Neoplasm; Tumor Cells, Cultured