Cancer chemotherapy and pharmacology
-
Cancer Chemother. Pharmacol. · Jan 1999
Multicenter Study Clinical TrialA phase II study of the effectiveness of docetaxel (Taxotere) in women with advanced breast cancer previously treated with polychemotherapy. Hellenic Cooperative Interhospital Group in Oncology.
The aim was to study the effectiveness of docetaxel (Taxotere) in patients with advanced breast cancer treated previously with polychemotherapy. ⋯ Docetaxel is an active second-line drug in advanced breast cancer. The time of relapse after cessation of anthracycline treatment may be a significant prognostic factor.
-
Cancer Chemother. Pharmacol. · Jan 1999
Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors.
Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children with malignant solid tumors. ⋯ Large interpatient variability was noted in topotecan pharmacokinetics, whereas intrapatient variability was relatively small. Further studies of oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further the interpatient variability.
-
Cancer Chemother. Pharmacol. · Jan 1999
Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors.
In order to assess the effect of the tyrosine kinase inhibitor CGP57148B on lineage-committed and primitive chronic myelogenous leukemia (CML) progenitor cells, peripheral blood progenitor cells (PBPC) mobilized in chronic phase CML were exposed to this compound in vitro. ⋯ The results support the use of CGP57148B either for short-term exposure in vitro (e.g. purging) or for continuous treatment of CML in vivo.
-
Cancer Chemother. Pharmacol. · Jan 1999
Characterization of MGI 114 (HMAF) histiospecific toxicity in human tumor cell lines.
The acylfulvenes are a class of antitumor agents derived from the fungal toxin illudin S. One acylfulvene derivative, MGI 114 (HMAF), demonstrates marked efficacy in xenograft carcinoma models when compared to the parent acylfulvene or related illudin compounds. The maximum tolerated dose (MTD) of the two analogs in animals, however, is similar. To help elucidate the basis of the increased therapeutic efficacy of MGI 114, we determined the in vitro cytotoxicity, cellular accumulation and DNA incorporation of this drug and compared the results with those from the parent acylfulvene analog. ⋯ The addition of a single methylhydroxyl group to acylfulvene to produce MGI 114 results in a marked increase in cytotoxicity in vitro towards tumor cells as demonstrated by the reduction in IC50 values. There was a corresponding decrease in the number of intracellular molecules of MGI 114 required to kill tumor cells, but no quantitative alteration in covalent binding of the drugs to DNA at equitoxic concentrations. This indicates that cellular metabolism plays a role in the in vitro cytotoxicity of MGI 114. The equivalent incorporation into genomic DNA at equitoxic doses suggests that DNA damage produced by acylfulvene and MGI 114 is equivalent in regard to cellular toxicity and ability to repair DNA. This increased cellular toxicity, together with the decrease in diffusion rate, may explain the increased therapeutic efficacy of MGI 114 as compared to the parent acylfulvene analog.
-
Cancer Chemother. Pharmacol. · Jan 1999
Clinical TrialPlasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial.
DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. ⋯ At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.