Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model?
OBJECTIVE
To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival.


METHODS
R3230 mammary adenocarcinomas (n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral paclitaxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defined survival end-point (3.0-cm diameter).


RESULTS
Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm ± 0.9 [standard deviation], 6.7 mm ± 0.6, 2.5 mm ± 0.6, respectively; P < .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation (P < .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 μg/g ± 0.35) and RF ablation-paclitaxel (9.28 μg/g ± 0.87) increased over that for paclitaxel (0.63 μg/g ± 0.25, P < .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean end-point survival for paclitaxel-RF ablation-doxorubicin (56.8 days ± 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days ± 2.5), RF ablation-doxorubicin (30.3 days ± 4.9, P < .002), or paclitaxel-doxorubicin (27.9 days ± 4.1, P < .001).


CONCLUSIONS
Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes.


BACKGROUND
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100500/-/DC1.
Yang
Wei
W
Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.
Ahmed
Muneeb
M
Elian
Mostafa
M
Hady
El-Shymma A
el-SA
Levchenko
Tatyana S
TS
Sawant
Rupa R
RR
Signoretti
Sabina
S
Collins
Michael
M
Torchilin
Vladimir P
VP
Goldberg
S Nahum
SN
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017115:Catheter Ablation; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D008081:Liposomes / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013194:Staining and Labeling
D006360:Heat-Shock Proteins; D008081:Liposomes; D004317:Doxorubicin; D017239:Paclitaxel