Intralesionally implanted cisplatin plus systemic carmustine for the treatment of brain tumor in rats.
OBJECTIVE
The benefit of conventional chemotherapy for the treatment of malignant brain tumors, although limited, is real. A major obstacle in the treatment of these lesions is the ability to deliver drug across the blood-brain barrier (BBB). Local drug implantation, circumventing the BBB, has been a useful strategy for treatment of intracranial lesions, and may work synergistically with systemic chemotherapy. To test this hypothesis, either intraperitoneal (i.p.) carmustine or cisplatin was combined with the intracranial (i.c.) administration of polymer-delivered cisplatin in rats with intracranial tumors.


RESULTS
9L gliosarcoma tumor cells (5 x 10(3)) were administered through a right frontal lobe cannula in rats 7 days prior to treatments. Cisplatin-loaded biodegradable polymer was then administered via the cannula, with free cisplatin or carmustine injected i.p. Animals were monitored for 60 days post-treatment. In experiment 1, i.c. cisplatin at a dose of 0.5, 1.0, 2.0, and 4.0 mg/m2 resulted in a mean survival time of 34 +/- 3, 39 +/- 14, 47 +/- 11, and 31 +/- 20 days (MST +/- SD), respectively, compared to 26 +/- 4 days in the control group and 30 +/- 7 days in the group treated with 50 mg/m2 i.p. free cisplatin. In experiment 2, i.p. free cisplatin at 25, 40, 50, and 100 mg/m2 resulted in a MST of 28 +/- 3, 30 +/- 4, 32 +/- 3, and 14 +/- 8 days, respectively, compared to 26 +/- 1 days in the control group. In experiment 3, the MST in the groups treated with 0.5 mg/m2 of i.c. cisplatin, 25 mg/m2 of i.p. cisplatin, 10 mg/kg of i.p. carmustine, i.c. cisplatin (0.5 mg/m2) plus i.p. cisplatin (25 mg/m2), and i.c. cisplatin (0.5 mg/m2) plus i.p. carmustine (10 mg/kg) was 30 +/- 4 days (P > 0.05), 28 +/- 2 (P > 0.05), 36 +/- 4 (P < 0.01), 32 +/- 3 (P < 0.01), and 50 +/- 11 days (P < 0.01), respectively, compared to the tumor control group (26 +/- 1 days). Long-term survivors (29%) were seen only in the i.c. cisplatin plus i.p. carmustine group. Additive toxicity was not observed.


CONCLUSIONS
Intralesional polymer-delivered (i.c.) cisplatin plus systemic (i.p.) carmustine is highly effective for the treatment of intracranial 9L gliosarcoma in tumors.
Kong
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Q
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA. qing.kong@uchsc.edu
Kleinschmidt-DeMasters
B K
BK
Lillehei
K O
KO
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage*; D002408:Catheters, Indwelling; D002945:Cisplatin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D018316:Gliosarcoma / Q000188:drug therapy*; D015552:Injections, Intralesional; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002945:Cisplatin; D002330:Carmustine