Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1998
Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro.
The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --> T and C --> S), and (3) TPT or SN-38 followed by cisplatin (T --> C and S --> C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. ⋯ After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.
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Cancer Chemother. Pharmacol. · Jan 1998
Comparative StudyCharacterization of acylfulvene histiospecific toxicity in human tumor cell lines.
Acylfulvene derivatives demonstrate marked efficacy in xenograft carcinoma models as compared with the parent illudin compounds. To elucidate the increased therapeutic efficacy of acylfulvene analogs, we compared them with the illudin compounds in terms of their in vitro cytotoxicity, cellular accumulation and DNA incorporation. ⋯ The combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.
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Cancer Chemother. Pharmacol. · Jan 1998
In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems.
Topotecan, a camptothecin analogue, is a specific inhibitor of topoisomerase I approved for use in the treatment of patients with refractory ovarian carcinoma. The drug's mechanism of action suggests a potential efficacy of drug combinations incorporating DNA-damaging agents. In an attempt better to define a rational basis for drug combination we examined the effect of topotecan on the cytotoxicity and antitumor activity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor xenograft. ⋯ However, an increase in the topotecan dose (7.1 mg/kg) was associated with an evident increase in the toxicity of the combination, thereby suggesting that the drug interaction was not tumor-specific. Although the molecular basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest of topoisomerase I inhibitors in combination with cisplatin.
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Cancer Chemother. Pharmacol. · Jan 1998
Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates.
The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. ⋯ Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.
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Cancer Chemother. Pharmacol. · Jan 1997
Multicenter Study Comparative Study Clinical TrialAll-trans retinoic acid therapy for newly diagnosed acute promyelocytic leukemia: comparison with intensive chemotherapy. The Japan Adult Leukemia Study Group (JALSG).
We analyzed the results of treating patients with newly diagnosed acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in the JALSG AML-92 study and compared them with those of the AML-87 and AML-89 studies, which consisted of standard chemotherapy. In the AML-92 study, patients were scheduled to receive 45 mg/ m2 oral ATRA daily until achievement of a complete remission (CR). If patients had initial leukocyte counts of > 3.0 x 10(9)/l, they received 40 mg/m2 daunorubicin (DNR) for 3 days and 200 mg/m2 behenoyl cytarabine (BHAC) for 5 days in addition to ATRA. ⋯ There was a significant difference in DFS between AML-92 and AML-87 (P = 0.0418) but not between AML-92 and AML-89 (P = 0.0687). In contrast, significant differences in EFS between AML-92 and both AML-87 (P = 0.0129) and AML-89 (P = 0.005) were observed. These results suggest that non-cross-resistant therapy combined with ATRA and intensive chemotherapy for APL contributes synergistically to the significant improvement in EFS.