Effects of verapamil and degradable starch microspheres during hepatic artery infusion of doxorubicin.
Chemotherapeutic tumoricidal activity may be enhanced by altering regional blood flow between host organ and tumor by transient embolization with degradable starch microspheres (DSMs) or by altering cellular drug transport with drugs such as verapamil. This study evaluated the effects of intraarterial verapamil and DSMs on hemodynamics and doxorubicin tissue levels. Rabbits (n = 34) with hepatic VX-2 carcinomas underwent hepatic artery infusion of doxurubicin (3 mg/kg) alone, with two doses of verapamil, and with verapamil plus DSMs. Blood pressure and heart rate were monitored, and heart, liver, and tumor tissue was obtained after 30 or 90 minutes. After verapamil (2 mg/kg) alone, mean heart rate decreased but infusion of verapamil plus DSMs resulted in only a 14% decrease in mean heart rate. Thirty minutes after drug infusions, mean hepatic tissue levels of doxorubicin were increased significantly by 2 mg/kg of verapamil compared with results with 1 mg/kg of verapamil and those in control groups (p less than 0.05). Mean tumor doxorubicin levels were not significantly different with verapamil alone. Verapamil plus DSMs or DSMs alone resulted in significantly lower mean hepatic and myocardial levels and increased mean tumor/liver ratios of doxorubicin after 90 minutes, compared with results in control or verapamil-alone groups. These results suggest that hepatic tumor drug levels are more affected by changes in regional blood flow with DSMs than by cellular drug transport changes caused by calcium channel blockers such as verapamil.
Thom
A K
AK
Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia 19104.
Zhang
S Z
SZ
Deveney
C
C
Daly
J M
JM
D000818:Animals; D001646:Bile / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004621:Embolization, Therapeutic; D006439:Hemodynamics / Q000187:drug effects; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D008099:Liver / Q000378:metabolism; D008863:Microspheres; D011817:Rabbits; D013213:Starch; D014700:Verapamil / Q000494:pharmacology*
D004317:Doxorubicin; D013213:Starch; D014700:Verapamil