Relationship between drug delivery and the intra-arterial infusion rate of SarCNU in C6 rat brain tumor model.
The influences of the flow rate on the concentration and distribution of drug in the rat brains and brain tumors after intra-arterial (intra-carotid) administration of [3H]SarCNU (sarcosinamide chloroethyl-1-nitrosourea) were examined. Results obtained at three flow rates via intra-carotid route were compared to those obtained with intravenous administrations. Adult female Wistar rats bearing C6 brain tumor were randomized into four-groups. Groups 1 (G.1) to 3 (G.3) received intra-arterial injection and Group 4 (G.4) received intravenous administration of [3H]SarCNU. G.1 (slow infusion rate) was administered 1 ml of [3H]SarCNU solution over 60 min (0.017 ml/min), Group 2 (G.2; medium infusion rate): 0.2 ml over 5 min (0.04 ml/min), G.3 (fast infusion rate): 1 ml over 5 min (0.2 ml/min), and G.4 (intravenous infusion): 1 ml intravenously over 5 min. Quantitative autoradiographic method was used to measure the concentration and the distribution of [3H]SarCNU in the brain and the brain tumors. The tissue uptake constant of SarCNU in both viable (tumor tissue excluding necrosis) and peak regions (the area of tumor containing top 20% of the tracer concentration) of the intra-arterial injection groups were significantly higher (p < 0.0001) than those in the intravenous group. The mean concentrations of the viable tumor in the intra-arterial groups were 2.92 (G.1), 16.06 (G.2), and 20.8 (G.3) times higher than those of intravenous group. Between the intra-arterial groups, the mean concentration in the viable tumors of G.1 (slow flow rate) was significantly (p < 0.0001) lower than in G.2 and G.3. However, there was no significant difference between G.2 and G.3. In three intra-arterial groups the mean concentration delivery ratios of the brain tumors were high and ranged from 3.07 (G.3) to 3.87 (G.2), but there was no significant difference between them. Only G.4, intravenous group, showed significantly (p < 0.005) lower concentration delivery ratio, 1.26. These results suggest that higher infusion rate in the intra-arterial chemotherapy could have an effect not only on the streaming phenomenon which results in the brain toxicities, but also on the increase in the concentration and the sufficient distribution of a drug in tumors. By finding chemotherapeutic agents to which tumors show high sensitivity and using intra-arterial administration of these agents at more effective flow rate, better clinical results could be achieved in the treatment of patients with malignant brain tumors.
Takeda
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N
Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Quebec, Canada.
Diksic
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M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002330:Carmustine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002460:Cell Line; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D007261:Infusions, Intra-Arterial / Q000379:methods; D007269:Injections, Intra-Arterial; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014316:Tritium
D000970:Antineoplastic Agents; D014316:Tritium; C044565:2-((((2-chloroethyl)nitrosoamino)carbonyl)amino)propanamide; D002330:Carmustine