Iron-targeting antitumor activity of gallium compounds and novel insights into triapine(®)-metal complexes.
CONCLUSIONS
Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents.


BACKGROUND
Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors.


RESULTS
Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed.


CONCLUSIONS
The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it.
Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. chitambr@mcw.edu
Christopher R
CR
Chitambar
William E
WE
Antholine
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005708:Gallium / Q000737:chemistry*; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018716:Molecular Mimicry; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*; D013882:Thiosemicarbazones / Q000737:chemistry*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D005708:Gallium; D007501:Iron