Improved tumor destruction with arsenic trioxide and radiofrequency ablation in three animal models.
OBJECTIVE
To assess the extent of tumor blood flow reduction that is achievable with arsenic trioxide (As2O3) and the effect of As2O3 on radiofrequency (RF)-induced coagulation.


METHODS
All animal protocols and experiments were approved by an institutional animal care and use committee before the start of the study. Experiments were conducted in three tumor models: intrarenal VX2 sarcoma in 27 rabbits, RCC 786-0 human renal cell carcinoma in 24 nude mice, and R3230 mammary adenocarcinoma in 40 rats. One dose (0-7.5 mg per kilogram of body weight) of As2O3 was administered (intraperitoneally in rodents, intravenously in rabbits) 1, 6, or 24 hours before standardized RF ablation, which was performed by using a 1-cm active tip, with mean temperatures of 70 degrees C +/- 2 (standard deviation) for 5 minutes in rodents and 90 degrees C +/- 2 for 6 minutes in rabbits. Laser Doppler flowmetry was used to quantify changes in blood flow, which were compared with diameters of induced tumor coagulation. Comparisons between groups were performed by using Student t tests or analysis of variance. The strengths of correlations between As2O3, tumor blood flow, and RF-induced coagulation were assessed by using linear and higher-order regression models and reported as R2 computations.


RESULTS
Administration of As2O3 significantly (P < .05) reduced blood flow and increased tumor destruction in all tumor models. In VX2 sarcoma tumors, 1 mg/kg As2O3 reduced mean tumor blood flow to 46% +/- 13 of the normal value. The mean resultant coagulation (1.1 cm +/- 0.1) was significantly greater than that achieved with RF ablation alone (0.6 cm +/- 0.1, P < .01). In RCC 786-0 and R3230 tumors, 5 mg/kg As2O3 reduced mean tumor blood flow to 57% +/- 6 and 46% +/- 6 of normal, respectively, increasing mean ablation extent to 0.8 cm +/- 0.1 for both models, compared with those achieved with the control treatment (0.6 cm +/- 0.1 and 0.5 cm +/- 0.1, respectively; P < .05 for both comparisons). Dose studies revealed correlations between drug dose, tumor blood flow, and RF-induced coagulation in all three tumor models (R2 = 0.60-0.79). Maximal RF synergy was observed 1 hour after As2O3 administration.


CONCLUSIONS
As2O3 administration represents a transient noninvasive method of reducing tumor blood flow during RF ablation, enabling larger zones of tumor destruction in multiple tumor models.
Hines-Peralta
Andrew
A
Laboratory for Minimally Invasive Tumor Therapy, Department of Radiology, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, WCC 308B, Boston, MA 02215, USA.
Sukhatme
Vikas
V
Regan
Meredith
M
Signoretti
Sabina
S
Liu
Zheng-jun
ZJ
Goldberg
S Nahum
SN
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy; D017115:Catheter Ablation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow / Q000187:drug effects; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy
D000970:Antineoplastic Agents; D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D000077237:Arsenic Trioxide