Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel Journal Article
| Authors: | Chou, T. C.; Zhang, X. G.; Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K. A.; Bertino, J. R.; Danishefsky, S. J. |
| Article Title: | Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel |
| Abstract: | The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug- resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX-1 human mammary and HT-29 colon tumor), its effects were clearly superior against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects. |
| Keywords: | cancer chemotherapy; unclassified drug; doxorubicin; drug efficacy; nonhuman; antineoplastic agents; paclitaxel; antineoplastic agent; ovarian neoplasms; mouse; animals; mice; cell survival; etoposide; cancer cell culture; tumor xenograft; drug effect; drug resistance, neoplasm; tumor cells, cultured; structure activity relation; structure-activity relationship; breast neoplasms; vinblastine; cancer inhibition; drug mechanism; mice, nude; transplantation, heterologous; microtubule assembly; breast adenocarcinoma; thiazoles; macrolide; multidrug resistance; intravenous drug administration; epothilones; epothilone b; epothilone d; lactones; mitosis inhibition; intraperitoneal drug administration; leukemia, t-cell, acute; cancer; humans; female; priority journal; article; desoxyepothilone b; leukemia p388 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 95 |
| Issue: | 26 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1998-12-22 |
| Start Page: | 15798 |
| End Page: | 15802 |
| Language: | English |
| DOI: | 10.1073/pnas.95.26.15798 |
| PUBMED: | 9861050 |
| PROVIDER: | scopus |
| PMCID: | PMC28124 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work