The effect of paclitaxel on the progression of polycystic kidney disease in rodents.
Woo et al (Nature 368:750-753) reported that parenteral administration of paclitaxel arrested the striking renal enlargement and prolonged life in C57BL/6J-cpk/cpk mice with a rapidly progressive form of polycystic kidney disease (PKD). In the current study, we sought to determine whether paclitaxel could alter the progression of other forms of hereditary PKD in rodents. Paclitaxel was administered by intraperitoneal injection to C57BL/6J-cpk/cpk mice and Han:SPRD-Cy/Cy rats with rapidly progressive PKD and to DBA/2FG-pcy/pcy mice and Han:SPRD-Cy/+ rats with slowly progressive PKD. Paclitaxel (150 micrograms/wk) prolonged the survival of cpk/cpk mice from 24.5 days to more than 65 days and decreased kidney weight relative to body weight from 16.5% at 21 days of age to 8.2% at more than 65 days of age. Mortality attributable to paclitaxel was 12%. By contrast, the administration of paclitaxel (0.1 to 15 mg/kg/wk) to 7- to 10-day-old Han:SPRD-Cy/Cy rats with rapidly progressive PKD had no effect on the course of the disease; moreover, paclitaxel caused severe side effects and premature death in all the Cy/Cy animals. Heterozygous male Cy/+ rats develop slowly progressive renal enlargement and azotemia. Paclitaxel, administered at 7, 15, or 27 mg/kg/wk to male Cy/+ rats from 4 until 10 weeks of age, reduced body weight gain, had an inconsistent effect on kidney weight relative to body weight, and had no effect on the serum urea nitrogen concentration. Mortality associated with the 7, 15, and 27 mg/kg/wk doses of paclitaxel was 0%, 15.4%, and 28.5%, respectively. DBA/2FG-pcy/pcy mice of either sex developed slowly progressive renal enlargement and azotemia. The administration of paclitaxel (100 to 150 micrograms/wk) from 2 to 10 weeks of age to DBA/2FG-pcy/pcy mice with cystic disease had no effect on the increase in kidney weight or on the level of serum urea nitrogen in comparison to untreated cystic animals. Mortality associated with 100- and 150-micrograms/wk doses of paclitaxel was 0% and 20%, respectively. We conclude that paclitaxel diminished the rate of renal enlargement and increased the life span of cpk/cpk mice but not Cy/Cy rats with rapidly progressive forms of PKD. Paclitaxel had no apparent benefit in Cy/+ rats nor pcy/pcy mice with slowly progressive PKD. On the basis of these studies in rodents, it appears that paclitaxel has limited potential usefulness as a therapeutic agent in the treatment of PKD.
Martinez
J R
JR
Department of Medicine, University of Kansas Medical Center, Kansas City 66160, USA.
Cowley
B D
BD
Gattone
V H
VH
Nagao
S
S
Yamaguchi
T
T
Kaneta
S
S
Takahashi
H
H
Grantham
J J
JJ
D000818:Animals; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000627:therapeutic use*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012076:Renal Agents / Q000627:therapeutic use*
D012076:Renal Agents; D017239:Paclitaxel