TY - JOUR
T1 - Pharmacokinetics and antitumor effects of mitoxantrone after intratumoral or intraarterial hepatic administration in rabbits
AU - Ramirez, Luis H.
AU - Zhao, Zhongxin
AU - Rougier, Philippe
AU - Bognel, Caroline
AU - Dzodic, Radan
AU - Vassal, Gilles
AU - Ardouin, Patrice
AU - Gouyette, Alain
AU - Munck, Jean Nicolas
PY - 1996/1/26
Y1 - 1996/1/26
N2 - The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 ± 62%), i.a.h. mitoxantrone (337 ± 110%), and i.t. ethanol treatments (287 ± 117%) as compared with control values (886 ± 223%; p < 0.01). Treatment with i.v. mitoxantrone (816 ± 132%) had no antitumor effect, nor did NaCl injections (868 ± 116%). Mitoxantrone given i.t. induced the highest antitumor effects. resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p < 0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.
AB - The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 ± 62%), i.a.h. mitoxantrone (337 ± 110%), and i.t. ethanol treatments (287 ± 117%) as compared with control values (886 ± 223%; p < 0.01). Treatment with i.v. mitoxantrone (816 ± 132%) had no antitumor effect, nor did NaCl injections (868 ± 116%). Mitoxantrone given i.t. induced the highest antitumor effects. resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p < 0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.
KW - Experimental liver tumors
KW - Intratumoral injections
KW - Mitoxantrone
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0030052813&partnerID=8YFLogxK
U2 - 10.1007/s002800050399
DO - 10.1007/s002800050399
M3 - Article
C2 - 8548884
AN - SCOPUS:0030052813
SN - 0344-5704
VL - 37
SP - 371
EP - 376
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -