Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts.
BACKGROUND
Epothilone compounds (e.g. epothilones A and B) represent a new structural class of microtubule inhibitors with the remarkable ability to inhibit tumor growth of multidrug-resistant cell lines at low nanomolar or even subnanomolar concentrations. Unfortunately, this therapeutic efficacy has only been achieved to date with a narrow therapeutic window. Hence, other structural analogs of compounds such as epothilone B are currently being synthesized in the hope that they will demonstrate equivalent antitumor efficacy with reduced systemic toxicity.


OBJECTIVE
To evaluate the relative efficacy and toxicity of selectively modified epothilone compounds.


METHODS
Compounds were initially screened for relative cytotoxicity against the human prostate cancer cell lines PC3, LNCaP, MDA PCa 2a and MDA PCa 2b. Growth inhibitory IC50 values of 0.5 to 4 nM were obtained. From this initial screen, one epothilone compound, 26-fluoroepothilone B, was chosen for further evaluation against the growth of s.c.-implanted MDA PCa 2b- and PC3-derived prostate tumors in athymic nude mice. The compound was administered intravenously at 2, 5 and 10 mg/kg after the tumors had reached 300 mm3. Two control groups were used: paclitaxel (40 mg/kg) and saline.


RESULTS
Following treatment with 10 mg 26-fluoroepothilone B/kg, there was a sustained decrease in tumor size for 30 days reaching a maximal reduction of 80% when compared with tumor growth in the saline control group. Sustained suppression (> 20 days) of tumor growth was observed following the second drug injection. Although a maximal body weight loss of 30% occurred after the second injection, all mice completely regained their initial body weight in 20 days. A lower dose (2 mg/kg) produced a 58% maximal reduction in tumor size and a 20% body weight loss. Minimal inhibition of tumor growth, however, was obtained with paclitaxel at a maximally tolerated dose (40 mg/kg). Other epothilones tested were either less effective and/or more toxic than 26-fluoroepothilone B. This new fluorinated epothilone compound supports the growth of paclitaxel-dependent Tax-18 mutant CHO cells and produces microtubule bundles similar to those produced by paclitaxel, indicating that the two drugs share a similar mechanism of action.


CONCLUSIONS
A new fluorinated epothilone compound, 26-fluoroepothilone B, has been described that stabilizes microtubule structures based on its support of growth of a mutant paclitaxel-dependent CHO cell line. Its antitumor activity against human prostate cancer in nude mice is superior to that of paclitaxel at equivalent toxic doses. Further research is required to determine optimal dosing strategies and to fully assess the compound's activity against other malignant diseases.
Newman
R A
RA
Pharmaceutical Development Center, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Yang
J
J
Raymond
M
M
Finlay
V
V
Cabral
F
F
Vourloumis
D
D
Stephens
L C
LC
Troncoso
P
P
Wu
X
X
Logothetis
C J
CJ
Nicolaou
K C
KC
Navone
N M
NM
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones; D006801:Humans; D007262:Infusions, Intravenous; D018942:Macrolides / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C439828:26-fluoroepothilone B; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D018942:Macrolides; D017239:Paclitaxel; C093788:epothilone B