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Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program.

Publication ,  Journal Article
Houghton, PJ; Morton, CL; Gorlick, R; Lock, RB; Carol, H; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Kolb, EA; Wu, J; Wozniak, AW ...
Published in: Mol Cancer Ther
January 2010

Rapamycin demonstrated broad-spectrum tumor growth inhibition activity against the in vivo panels of childhood tumors used in the Pediatric Preclinical Testing Program (PPTP). Here we have evaluated rapamycin combined with agents used frequently in the treatment of childhood malignancies. Rapamycin was tested in vitro against 23 cell lines alone or in combination with melphalan, cisplatin, vincristine, or dexamethasone (leukemic models only). In vivo, the impact of combining rapamycin with a cytotoxic agent was evaluated using two measures: 1) the therapeutic enhancement measure, and 2) a linear regression model for time-to-event to formally evaluate for sub- and supraadditivity for the combination compared to the agents used alone. Combining rapamycin with cytotoxic agents in vitro gave predominantly subadditive or additive effects, except for dexamethasone in leukemia models for which supra-additive activity was observed. In vivo testing demonstrated that therapeutic enhancement was common for rapamycin in combination with cyclophosphamide and occurred for 4 of 11 evaluable xenografts for the rapamycin and vincristine combination. The combinations of rapamycin with either cyclophosphamide or vincristine were significantly more effective than the respective standard agents used alone at their maximum tolerated doses (MTD) for most evaluable xenografts. The combination of rapamycin and cisplatin produced excessive toxicity requiring cisplatin dose reductions, and therapeutic enhancement was not observed for this combination. Addition of rapamycin to either cyclophosphamide or vincristine at their respective MTDs appears promising, as these combinations are relatively well tolerated and as many of the pediatric preclinical models evaluated demonstrated therapeutic enhancement for these combinations.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

January 2010

Volume

9

Issue

1

Start / End Page

101 / 112

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sirolimus
  • Oncology & Carcinogenesis
  • Models, Biological
  • Mice, SCID
  • Mice
  • Leukemia
  • Humans
  • Cyclophosphamide
  • Child
 

Citation

APA
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MLA
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Houghton, P. J., Morton, C. L., Gorlick, R., Lock, R. B., Carol, H., Reynolds, C. P., … Smith, M. A. (2010). Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther, 9(1), 101–112. https://doi.org/10.1158/1535-7163.MCT-09-0952
Houghton, Peter J., Christopher L. Morton, Richard Gorlick, Richard B. Lock, Hernan Carol, C Patrick Reynolds, Min H. Kang, et al. “Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program.Mol Cancer Ther 9, no. 1 (January 2010): 101–12. https://doi.org/10.1158/1535-7163.MCT-09-0952.
Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther. 2010 Jan;9(1):101–12.
Houghton, Peter J., et al. “Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program.Mol Cancer Ther, vol. 9, no. 1, Jan. 2010, pp. 101–12. Pubmed, doi:10.1158/1535-7163.MCT-09-0952.
Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, Kang MH, Maris JM, Keir ST, Kolb EA, Wu J, Wozniak AW, Billups CA, Rubinstein L, Smith MA. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther. 2010 Jan;9(1):101–112.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

January 2010

Volume

9

Issue

1

Start / End Page

101 / 112

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sirolimus
  • Oncology & Carcinogenesis
  • Models, Biological
  • Mice, SCID
  • Mice
  • Leukemia
  • Humans
  • Cyclophosphamide
  • Child