The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice Journal Article
| Authors: | Chou, T. C.; O'Connor, O. A.; Tong, W. P.; Guan, Y.; Zhang, Z. G.; Stachel, S. J.; Lee, C.; Danishefsky, S. J. |
| Article Title: | The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice |
| Abstract: | We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM/VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC50 values were 0.029, 0.092, 2.99, and 5.17 μM, respectively. These values represent 4-, 33.5-, 1,423- and 3,133-fold resistance, respectively, when compared with the corresponding IC50 in the parent [nonmultiple drug-resistant (MDR)] CCRF-CEM cells. We then produced MDR human lung carcinoma A549 cells by continuous exposure of the tumor cells to sublethal concentrations of dEpoB (1.8 yr), vinblastine (1.2 yr), and paclitaxel (1.8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins. |
| Keywords: | cancer chemotherapy; unclassified drug; human cell; drug efficacy; drug safety; nonhuman; antineoplastic agents; paclitaxel; antineoplastic agent; animal cell; mouse; animals; mice; tumor volume; animal experiment; animal model; drug structure; tumor xenograft; drug synthesis; vinblastine; animalia; mus musculus; nude mouse; mice, nude; cancer cell; neoplasms, experimental; transplantation, heterologous; microtubule assembly; lung carcinoma; neoplasm transplantation; ic 50; thiazoles; microtubules; multidrug resistance; ixabepilone; epothilones; epothilone d; epothilone derivative; growth inhibition; lactones; drug solubility; 12,13 desoxyepothilone b; humans; human; male; priority journal; article; 12,13 desoxyepothilone f; 15 desoxy 15 azaepothilone |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 98 |
| Issue: | 14 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2001-07-03 |
| Start Page: | 8113 |
| End Page: | 8118 |
| Language: | English |
| DOI: | 10.1073/pnas.131153098 |
| PUBMED: | 11438750 |
| PROVIDER: | scopus |
| PMCID: | PMC35476 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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