The influence of recombinant human insulin-like growth factor-I (rhIGF- I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models

Corrie E.M. Gidding, Glen S. Germain, Michael B. Dilling, Tiny G.J. Meeuwsen-de Boer, Richard A. Ashmun, Siebold S.N. De Graaf, Karen A. Veverka, Willem A. Kamps, Peter J Houghton

Research output: Contribution to journalArticle

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Abstract

Purpose: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting side effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growth of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore, studies performed have been done under serum-free conditions, which are far from physiological. Methods: We studied the influence of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and determined the effects of vincristine, rhIGF-I or their combination on tumor growth. Results: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimulated growth of both cell lines. Exposure to cytotoxic drugs with and without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF- I. However, relative to the appropriate control, fractional growth inhibition and or cell kill of the cytotoxic drugs was identical with and without rhIGF- I. Under serum-containing conditions, rhIGF-I had no effect on cell growth or drug cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. Conclusions: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs under serum-containing conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

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Rhabdomyosarcoma
Cell growth
Cytotoxicity
Insulin-Like Growth Factor I
Heterografts
Cells
Vincristine
Cell Line
Growth
Pharmaceutical Preparations
Serum
Tumors
Bearings (structural)
Neoplasms
70-kDa Ribosomal Protein S6 Kinases
Topotecan
Antimitotic Agents
IGF Type 1 Receptor
Etoposide
Doxorubicin

Keywords

  • Cytotoxicity
  • IGF-I
  • Vincristine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

The influence of recombinant human insulin-like growth factor-I (rhIGF- I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models. / Gidding, Corrie E.M.; Germain, Glen S.; Dilling, Michael B.; Meeuwsen-de Boer, Tiny G.J.; Ashmun, Richard A.; De Graaf, Siebold S.N.; Veverka, Karen A.; Kamps, Willem A.; Houghton, Peter J.

In: Cancer Chemotherapy and Pharmacology, Vol. 45, No. 1, 01.01.2000, p. 21-30.

Research output: Contribution to journalArticle

Gidding, Corrie E.M. ; Germain, Glen S. ; Dilling, Michael B. ; Meeuwsen-de Boer, Tiny G.J. ; Ashmun, Richard A. ; De Graaf, Siebold S.N. ; Veverka, Karen A. ; Kamps, Willem A. ; Houghton, Peter J. / The influence of recombinant human insulin-like growth factor-I (rhIGF- I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models. In: Cancer Chemotherapy and Pharmacology. 2000 ; Vol. 45, No. 1. pp. 21-30.
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AU - Germain, Glen S.

AU - Dilling, Michael B.

AU - Meeuwsen-de Boer, Tiny G.J.

AU - Ashmun, Richard A.

AU - De Graaf, Siebold S.N.

AU - Veverka, Karen A.

AU - Kamps, Willem A.

AU - Houghton, Peter J

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N2 - Purpose: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting side effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growth of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore, studies performed have been done under serum-free conditions, which are far from physiological. Methods: We studied the influence of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and determined the effects of vincristine, rhIGF-I or their combination on tumor growth. Results: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimulated growth of both cell lines. Exposure to cytotoxic drugs with and without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF- I. However, relative to the appropriate control, fractional growth inhibition and or cell kill of the cytotoxic drugs was identical with and without rhIGF- I. Under serum-containing conditions, rhIGF-I had no effect on cell growth or drug cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. Conclusions: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs under serum-containing conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children.

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