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Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors.

Publication ,  Journal Article
Houghton, PJ; Cheshire, PJ; Hallman, JD; Lutz, L; Friedman, HS; Danks, MK; Houghton, JA
Published in: Cancer Chemother Pharmacol
1995

The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1995

Volume

36

Issue

5

Start / End Page

393 / 403

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Topotecan
  • Topoisomerase I Inhibitors
  • Rhabdomyosarcoma
  • Random Allocation
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice, Inbred CBA
  • Mice
 

Citation

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Chicago
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MLA
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Houghton, P. J., Cheshire, P. J., Hallman, J. D., Lutz, L., Friedman, H. S., Danks, M. K., & Houghton, J. A. (1995). Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol, 36(5), 393–403. https://doi.org/10.1007/BF00686188
Houghton, P. J., P. J. Cheshire, J. D. Hallman, L. Lutz, H. S. Friedman, M. K. Danks, and J. A. Houghton. “Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors.Cancer Chemother Pharmacol 36, no. 5 (1995): 393–403. https://doi.org/10.1007/BF00686188.
Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, et al. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36(5):393–403.
Houghton, P. J., et al. “Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors.Cancer Chemother Pharmacol, vol. 36, no. 5, 1995, pp. 393–403. Pubmed, doi:10.1007/BF00686188.
Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, Houghton JA. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36(5):393–403.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1995

Volume

36

Issue

5

Start / End Page

393 / 403

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Topotecan
  • Topoisomerase I Inhibitors
  • Rhabdomyosarcoma
  • Random Allocation
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice, Inbred CBA
  • Mice