Anti-tumor effect of combination therapy with intratumoral controlled-release paclitaxel (PACLIMER microspheres) and radiation.
BACKGROUND
Paclitaxel is one of the few chemotherapeutics effective in patients with advanced protstate cancer. Paclitaxel has also been reported to have radiosensitizing effects in prostate cancer. Local delivery of a controlled-release paclitaxel product may allow for increase local concentrations of paclitaxel at the tumor site and, in conjunction with radiation, may enhance cell kill by its radiosensitization mechanism.


METHODS
Orthotopic LNCaP tumors were injected with 40% PACLIMER Microspheres (40% loading; w:w) when tumors were 100-200 mm(3). Twenty-eight days post cell injection, mice were sacrificed, tumors weighed, and serum measured for PSA. TSU-xenografts were injected with PACLIMER Microspheres (10% and 40% loaded; w:w) or placebo microspheres when the tumors were approximately 100 mm(3). Half of xenograft tumors were irradiated with a single dose (10 Gy) of radiation. Tumor volume was followed over time.


RESULTS
Forty percent PACLIMER Microspheres significantly reduced tumor growth in the LNCaP orthotopic model. PSA was a good indicator of response. Forty percent PACLIMER Microspheres had a significant effect on slowing TSU growth compared to placebo microspheres. Addition of a single acute dose of radiation significantly enhanced the effect of 10% PACLIMER Microspheres (P < 0.05), had minimal effect on 40% PACLIMER Microspheres, and no enhancing effect on tumors treated with placebo microspheres.


CONCLUSIONS
A controlled-release formulation of paclitaxel can be very effective in the treatment of prostate cancer. Additionally, PACLIMER Microspheres may be effectively used as a radiosensitizer in genitourinary cancers.
Lapidus
Rena G
RG
Guilford Pharmaceuticals, Inc., Baltimore, Maryland, USA.
Dang
Wenbin
W
Rosen
David Marc
DM
Gady
Alyssa M
AM
Zabelinka
Yelena
Y
O'Meally
Robert
R
DeWeese
Theodore L
TL
Denmeade
Samuel R
SR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008863:Microspheres; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*
D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel