Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route Journal Article
| Authors: | Chou, T. C.; Dong, H.; Zhang, X.; Tong, W. P.; Danishefsky, S. J. |
| Article Title: | Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route |
| Abstract: | Epothilones, 16-membered macrolides isolated from a myxobacterium in soil, exert their antitamor effect, like Taxol, by induction of microtubule polymerization and microtabule stabilization. They are effective against tumor cells that are resistant to Taxol or vinblastine. We recently designed, via molecular editing and total synthesis, a new class of epothilones represented by 26-triflnoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1 human mammary carcinoma xenografts (as large as 3.4% body weight) with Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d × 5, q3d × 4) led to complete disappearance and de facto "cure" (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with Taxol and Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d × 4) ×3] against HCT-116 human colon carcinoma xenografts revealed that both drugs achieved tumor remission; however, all Taxol-treated mice relapsed in ∼1.3 months, whereas the Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore, tumor remission was achieved by Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the Taxol-resistant CCRF-CEM/Taxol (leukemia) xenograft tumors. Most remarkably, p.o. administration of Fludelone (30 mg/kg, q2d × 7, q2d × 9, q2d × 5) against MK-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that Fludelone is a highly promising compound for cancer chemotherapeutics. ©2005 American Association for Cancer Research. |
| Keywords: | controlled study; treatment outcome; unclassified drug; human cell; drug efficacy; nonhuman; antineoplastic agents; capecitabine; paclitaxel; antineoplastic agent; neoplasms; mouse; animals; mice; bolus injection; animal experiment; animal model; antineoplastic activity; cancer cell culture; tumor xenograft; drug resistance, neoplasm; drug screening assays, antitumor; xenograft model antitumor assays; cell line, tumor; drug synthesis; structure activity relation; vinblastine; cancer resistance; cancer regression; nude mouse; mice, nude; breast carcinoma; cancer relapse; microtubule assembly; maximum tolerated dose; colon carcinoma; administration, oral; microtubules; macrolide; infusions, intravenous; epothilones; epothilone b; epothilone d; epothilone derivative; myxococcales; fludelone; bms 310705; kos 1584; bms 243550 |
| Journal Title: | Cancer Research |
| Volume: | 65 |
| Issue: | 20 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-10-15 |
| Start Page: | 9445 |
| End Page: | 9454 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-05-1014 |
| PUBMED: | 16230408 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 23" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus" |
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