Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90yttrium-DOTA-peptide-ChL6.
BACKGROUND
Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-ChL6 (5.55 MBq;150 microCi) has resulted in durable responses. To make radioimmunotherapy (RIT) more effective, the radiation-enhancing drugs Taxol (paclitaxel) and Taxotere (docetaxel) were tested for synergy with 90Y-DOTA-peptide-ChL6.


METHODS
Nude mice bearing human prostate cancer PC3 xenografts were treated with 90Y-DOTA-peptide-ChL6 (2.78 MBq; 75 microCi) and after 24 hr, paclitaxel (300 or 600 microg), or docetaxel (300 microg). Tumor size, survival, blood counts, and pharmacokinetics were monitored to assess efficacy and toxicity.


RESULTS
Docetaxel plus RIT had a 67% cure rate, whereas no mice were cured among the RIT alone, chemotherapy alone, or untreated controls. Paclitaxel (600 microg) plus RIT produced a 100% response rate with 20% cures. Average tumor volume was reduced to a greater degree in the combined modality radioimmunotherapy (CMRIT) groups compared to controls and the anti-tumor response was durable. Myelotoxicity in the combined modality groups (RIT plus paclitaxel or RIT plus docetaxel) were similar to groups receiving the same dose of RIT alone.


CONCLUSIONS
In the PC3-tumor nude mouse model, addition of paclitaxel or docetaxel to 90Y-DOTA-peptide-ChL6, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.
O'Donnell
Robert T
RT
Department of Internal Medicine, Division of Hematology and Oncology, Section of Radiodiagnosis & Therapy, University of California Davis Medical Center, Sacramento, California 95816, USA. rtodonnell@ucdavis.edu
DeNardo
Sally J
SJ
Miers
Laird A
LA
Lamborn
Kathleen R
KR
Kukis
David L
DL
DeNardo
Gerald L
GL
Meyers
Frederick J
FJ
D000818:Animals; D003131:Combined Modality Therapy; D000077143:Docetaxel; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016499:Radioimmunotherapy; D043823:Taxoids; D014183:Transplantation, Heterologous; D015019:Yttrium / Q000008:administration & dosage* / Q000493:pharmacokinetics
D006571:Heterocyclic Compounds; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; C112391:yttrium-90-DOTA-peptide-chimeric L6; D000077143:Docetaxel; D015019:Yttrium; D017239:Paclitaxel