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.
OBJECTIVE
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.
Gidding
C E
CE
Children's Cancer Center, Beatrix Children's Hospital, Groningen, The Netherlands.
Germain
G S
GS
Dilling
M B
MB
Meeuwsen-de Boer
T G
TG
Ashmun
R A
RA
de Graaf
S S
SS
Veverka
K A
KA
Kamps
W A
WA
Houghton
P J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014750:Vincristine; D007334:Insulin-Like Growth Factor I