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Antineoplastic drugs that interfere with iron metabolism in cancer cells
J F Head1, F Wang, R L Elliott
1Mastology Research Institute, Elliott Mastology Center, Baton Rouge, LA 70816, USA.
Abstract:
Normal iron metabolism can be perturbed with iron chelators, toxic metals that bind to transferrin, toxic metals bound to transferrin or antineoplastic agents covalently linked to transferrin. These agents cause significant inhibition of tumor cell growth in cell culture and have been shown to have significant in vivo antineoplastic activity. Cell culture studies showed that deferoxamine mesylate inhibits cell growth and division in both the MCF-7 human breast and HeLa human cervical carcinoma cell lines. Animal studies demonstrated that when deferoxamine mesylate is injected intravenously into rats that are on a low iron diet, there is a significant reduction in the growth of 13762NF mammary adenocarcinomas. Gallium, indium and the antineoplastic agent cisplatin were bound to the iron binding site of transferrin and inhibit the growth of malignant carcinoma cell lines. Gallium-transferrin and indium-transferrin were at least 10 times more inhibitory to both MCF-7 and HeLa cell lines than their free salts. Further cell culture studies demonstrated that cisplatin-transferrin complexes act synergistically with doxorubicin to inhibit the growth of cultured MCF-7 cells. In a Phase I clinical trial of cisplatin-transferrin complex there was a 36% (four of 11 patients) response rate in breast cancer patients with advanced disease. In a second clinical study the sequential administration of deferoxamine mesylate (2 days at 6 g/day in 8 hrs), cisplatin-transferrin complex (7 days at 500 mg/day) and FAC (5-fluorouracil, doxorubicin and cyclophosphamide at 450, 45 and 450 mg/m2, respectively) to advanced breast cancer patients resulted in partial responses in seven of eight patients treated. Future work will concentrate on substituting transferrin based agents with daunorubicin or doxorubicin attached to the surface of the transferrin, and gallium or indium bound to the iron binding site, to increase efficacy of the second component of the sequential combination chemotherapy.
Insights
Iron chelators and metal-transferrin complexes show promise in cancer treatment by inhibiting tumor cell growth. Studies demonstrate significant antineoplastic activity in cell cultures and animal models, with clinical trials showing positive response rates in advanced breast cancer patients.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Iron metabolism plays a crucial role in cell proliferation, making it a target for cancer therapy.
- Iron chelators and metal-transferrin conjugates can disrupt tumor cell growth and exhibit antineoplastic properties.
Purpose of the Study:
- To investigate the efficacy of iron chelators and metal-transferrin complexes as anti-cancer agents.
- To evaluate the antineoplastic activity of deferoxamine mesylate, gallium-transferrin, indium-transferrin, and cisplatin-transferrin complexes in various cancer models.
Main Methods:
- Cell culture studies using MCF-7 (breast) and HeLa (cervical) carcinoma cell lines.
- In vivo studies involving animal models with mammary adenocarcinomas.
- Phase I and sequential clinical trials in advanced breast cancer patients.
Main Results:
- Deferoxamine mesylate inhibited cell growth and reduced tumor growth in animal models.
- Gallium-transferrin and indium-transferrin showed significantly higher inhibition than their free salts.
- Cisplatin-transferrin complexes demonstrated synergistic effects with doxorubicin and achieved a 36% response rate in a Phase I trial.
Conclusions:
- Transferrin-bound agents, including metal complexes and covalently linked drugs, represent a viable strategy for cancer therapy.
- Sequential administration of deferoxamine mesylate, cisplatin-transferrin, and FAC chemotherapy yielded high partial response rates in advanced breast cancer.
- Future research will focus on enhancing efficacy through targeted drug delivery and combination therapies.