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Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts.

Publication ,  Journal Article
Hare, CB; Elion, GB; Houghton, PJ; Houghton, JA; Keir, S; Marcelli, SL; Bigner, DD; Friedman, HS
Published in: Cancer Chemother Pharmacol
1997

Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The camptothecin derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin's lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1-5 and 8-12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P < 0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several tumor lines. Further, tumor regression was evident in every treated animal bearing a subcutaneous tumor, with some xenografts yielding complete tumor regression. Statistically significant (P < 0.001) increases in survival were demonstrated in the two intracranial xenografts-D341 EP (73.0% increase) and D-456 MG (114.2% increase)-treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1997

Volume

39

Issue

3

Start / End Page

187 / 191

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Topoisomerase I Inhibitors
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Irinotecan
  • Humans
  • Drug Screening Assays, Antitumor
 

Citation

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Hare, C. B., Elion, G. B., Houghton, P. J., Houghton, J. A., Keir, S., Marcelli, S. L., … Friedman, H. S. (1997). Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol, 39(3), 187–191. https://doi.org/10.1007/s002800050558
Hare, C. B., G. B. Elion, P. J. Houghton, J. A. Houghton, S. Keir, S. L. Marcelli, D. D. Bigner, and H. S. Friedman. “Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts.Cancer Chemother Pharmacol 39, no. 3 (1997): 187–91. https://doi.org/10.1007/s002800050558.
Hare CB, Elion GB, Houghton PJ, Houghton JA, Keir S, Marcelli SL, Bigner DD, Friedman HS. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol. 1997;39(3):187–191.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1997

Volume

39

Issue

3

Start / End Page

187 / 191

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Topoisomerase I Inhibitors
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Irinotecan
  • Humans
  • Drug Screening Assays, Antitumor