TY - JOUR
T1 - Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route
AU - Chou, Ting Chao
AU - Dong, Huajin
AU - Zhang, Xiuguo
AU - Tong, William P.
AU - Danishefsky, Samuel J.
PY - 2005/10/15
Y1 - 2005/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-05-1014
DO - 10.1158/0008-5472.CAN-05-1014
M3 - Article
C2 - 16230408
AN - SCOPUS:27144456478
SN - 0008-5472
VL - 65
SP - 9445
EP - 9454
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -