Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program

Peter J. Houghton, Christopher L. Morton, Richard Gorlick, Richard B. Lock, Hernan Carol, C. Patrick Reynolds, Min H. Kang, John M. Maris, Stephen T. Keir, E. Anders Kolb, Jianrong Wu, Amy W. Wozniak, Catherine A. Billups, Larry Rubinstein, Malcolm A. Smith

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)101-112
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Cytotoxins
Sirolimus
Pediatrics
Vincristine
Cyclophosphamide
Cisplatin
Heterografts
Dexamethasone
Linear Models
Neoplasms
Melphalan
Maximum Tolerated Dose
Therapeutics
Leukemia
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. Molecular Cancer Therapeutics, 9(1), 101-112. https://doi.org/10.1158/1535-7163.MCT-09-0952

Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program. / Houghton, Peter J.; Morton, Christopher L.; Gorlick, Richard; Lock, Richard B.; Carol, Hernan; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Keir, Stephen T.; Kolb, E. Anders; Wu, Jianrong; Wozniak, Amy W.; Billups, Catherine A.; Rubinstein, Larry; Smith, Malcolm A.

In: Molecular Cancer Therapeutics, Vol. 9, No. 1, 01.2010, p. 101-112.

Research output: Contribution to journalArticle

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 2010, 'Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program', Molecular Cancer Therapeutics, vol. 9, no. 1, pp. 101-112. https://doi.org/10.1158/1535-7163.MCT-09-0952
Houghton, Peter J. ; Morton, Christopher L. ; Gorlick, Richard ; Lock, Richard B. ; Carol, Hernan ; Reynolds, C. Patrick ; Kang, Min H. ; Maris, John M. ; Keir, Stephen T. ; Kolb, E. Anders ; Wu, Jianrong ; Wozniak, Amy W. ; Billups, Catherine A. ; Rubinstein, Larry ; Smith, Malcolm A. / Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 1. pp. 101-112.
@article{5a7c9742de6649f3bb00d88be8a86536,
title = "Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program",
abstract = "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.",
author = "Houghton, {Peter J.} and Morton, {Christopher L.} and Richard Gorlick and Lock, {Richard B.} and Hernan Carol and Reynolds, {C. Patrick} and Kang, {Min H.} and Maris, {John M.} and Keir, {Stephen T.} and Kolb, {E. Anders} and Jianrong Wu and Wozniak, {Amy W.} and Billups, {Catherine A.} and Larry Rubinstein and Smith, {Malcolm A.}",
year = "2010",
month = "1",
doi = "10.1158/1535-7163.MCT-09-0952",
language = "English (US)",
volume = "9",
pages = "101--112",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Stage 2 combination testing of rapamycin with cytotoxic agents by the pediatric preclinical testing program

AU - Houghton, Peter J.

AU - Morton, Christopher L.

AU - Gorlick, Richard

AU - Lock, Richard B.

AU - Carol, Hernan

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Maris, John M.

AU - Keir, Stephen T.

AU - Kolb, E. Anders

AU - Wu, Jianrong

AU - Wozniak, Amy W.

AU - Billups, Catherine A.

AU - Rubinstein, Larry

AU - Smith, Malcolm A.

PY - 2010/1

Y1 - 2010/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=73949122305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73949122305&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-09-0952

DO - 10.1158/1535-7163.MCT-09-0952

M3 - Article

C2 - 20053767

AN - SCOPUS:73949122305

VL - 9

SP - 101

EP - 112

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 1

ER -