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

Purpose: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting si de effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growt h of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet bee n studied. Furthermore, studies performed have been done under serum-free c onditions, which are far from physiological. Methods: We studied the influe nce of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and R h1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxo rubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and det ermined the effects of vincristine, rhIGF-I or their combination on tumor g rowth. Results: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase a fter stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimula ted 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. Ho wever, relative to the appropriate control, fractional growth inhibition an d 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 rh IGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. C onclusions: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs unde r serum-containing conditions in vitro or in tumor-bearing mice. Potentiall y, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children .