Antineoplastic drugs that interfere with iron metabolism in cancer cells.
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.
Head
J F
JF
Mastology Research Institute, Elliott Mastology Center, Baton Rouge, LA 70816, USA.
Wang
F
F
Elliott
R L
RL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003630:Daunorubicin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005708:Gallium / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007204:Indium / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D051381:Rats; D014168:Transferrin / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D014168:Transferrin; D007204:Indium; D005708:Gallium; D007501:Iron; D003676:Deferoxamine; D002945:Cisplatin; C027235:gallium nitrate; D003630:Daunorubicin