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Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies
1Department of Medicine, Cornell University Medical College, New York, N.Y.
Background:
A variety of human tumors frequently express high levels of epidermal growth factor (EGF) receptor and its ligand, transforming growth factor alpha (TGF-alpha), which in some tumors is associated with poor prognosis. Monoclonal antibodies (MAbs) that block the binding of TGF-alpha or EGF to the receptor can inhibit proliferation of tumor cells that express the receptor. Studies suggest that these MAbs may enhance the antitumor effects of chemotherapy.
Purpose:
Our purpose was to study, in vitro and in vivo, the antitumor effects of doxorubicin in combination with anti-EGF receptor MAbs against tumor cells expressing high levels of EGF receptor. Our goal was to achieve maximum initial cytoreduction with high-dose doxorubicin in association with prolonged blockade of EGF receptor with MAbs.
Methods:
Anti-EGF receptor MAbs 528 (isotype IgG2a) and 225 (isotype IgG1) were used in combination with doxorubicin against cells from human A431 squamous cell carcinoma and human MDA-468 breast adenocarcinoma. Both A431 and MDA-468 cells express high levels of EGF receptors and TGF-alpha. Cultured cells were treated with doxorubicin (range, 0-10 nM) in the presence or absence of MAb 528 or 225 (range, 0-30 nM). At 48 hours, doxorubicin-containing medium was removed, and treatment with antibody was continued for 5 days, when cell proliferation assays were performed. The activity of the agents and the combinations against well-established xenografts in BALB/c nude mice was also studied. In nude mice, doxorubicin was given at doses of 50-100 micrograms/20 g body weight on 2 successive days, and MAbs 528 and 225 were given at a dose range of 0-2 mg intraperitoneally twice a week.
Results:
MAbs 528 and 225 both enhanced the antitumor effects of doxorubicin against A431 and MDA-468 tumor cells, producing additive growth suppression in cell cultures. MAb 528 increased the antitumor effects of doxorubicin by 32%-42%, and similar results were obtained with MAb 225. In BALB/c athymic mice, the treatment of well-established xenografts with either doxorubicin or anti-EGF receptor MAb alone temporarily inhibited growth, but the combination of both agents substantially enhanced antitumor activity over that of doxorubicin alone in A431 and MDA-468 cell xenografts. The combination treatment of mice bearing A431 xenografts resulted in tumor eradication of 40%-100% in the surviving mice in several independent experiments. The enhanced antitumor activity was dose dependent.
Conclusions:
Our results suggest that anti-EGF receptor MAbs substantially enhance the effects of doxorubicin against well-established xenografts of tumor cells expressing high levels of EGF receptors.
Implications:
Clinical trials with anti-EGF receptor MAbs are being conducted, and trials with anti-EGF receptor MAbs combined with doxorubicin are planned.
Insights
Monoclonal antibodies targeting the epidermal growth factor (EGF) receptor significantly boost doxorubicin's effectiveness against tumors. This combination therapy shows promise for enhanced cancer treatment by improving cytoreduction and tumor eradication.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Human tumors often overexpress epidermal growth factor (EGF) receptor and transforming growth factor alpha (TGF-alpha), correlating with poor prognosis.
- Monoclonal antibodies (MAbs) blocking EGF/TGF-alpha binding to the receptor can inhibit tumor cell proliferation.
- MAbs may potentiate the antitumor effects of chemotherapy.
Purpose of the Study:
- To evaluate the combined antitumor effects of doxorubicin and anti-EGF receptor MAbs against human tumor cells with high EGF receptor expression.
- To achieve maximal initial cytoreduction with high-dose doxorubicin and prolonged EGF receptor blockade.
Main Methods:
- In vitro and in vivo studies using anti-EGF receptor MAbs (528 and 225) combined with doxorubicin.
- Treatment of A431 squamous cell carcinoma and MDA-468 breast adenocarcinoma cells/xenografts.
- Dosing regimens included doxorubicin (0-10 nM in vitro; 50-100 µg/20g body weight in vivo) and MAbs (0-30 nM in vitro; 0-2 mg in vivo).
Main Results:
- MAbs 528 and 225 synergistically enhanced doxorubicin's antitumor effects, causing additive growth suppression in vitro (32%-42% increase).
- In vivo xenograft models, the combination therapy substantially improved antitumor activity compared to doxorubicin alone.
- Combination treatment led to significant tumor eradication (40%-100%) in mice bearing A431 xenografts, demonstrating dose-dependent enhancement.
Conclusions:
- Anti-EGF receptor MAbs significantly enhance doxorubicin's efficacy against established xenografts of tumors overexpressing EGF receptors.
- Clinical trials combining anti-EGF receptor MAbs with doxorubicin are planned, building on promising preclinical data.