"Metal complexes as potential imaging agents and anti-cancer drugs"

            Medicinal, biochemical uses and application of metal complexes are of increasing importance due to news and issues regarding about detrimental effect of metal pollution that were great concern by government agencies. Series cases were reported about main threats to human health were associated to contamination of heavy metals such as lead, cadmium, nickel. These metals have been studied extensively and their effects on human health have been regularly reviewed by international agencies such as World Health Organization (WHO). Prior to these cases, metal complexes were used in advance as imaging agents in which the central metal ion is main feature of the mechanism of action. Some metal complexes were versatile as chelating agents to target carcinogenic form and may produce chiefly as anti-cancer drugs. The use of chelating agents is one of the good examples of how metal complexes ameliorated such rare diseases. Report studied by Sarkar, chelating agent is used as treatment of Wilson's disease due to free metal ion Cu(II) and had been optimized for research to gain results that may positively used for advance medical technology. Free metal ion astatine (At) in compound As₂O₃ is used as an anti-cancer agent for treatment in acute promyelocytic leukemia. Commercially used platinum in polynuclear Pt(IV) species with trade names BBR 3464, Satraplatin, and AMD-473 is used for as anti-cancer agents. The platinum metal complexes expands spectrum of activity of cisplatin or as chemotherapy agent. Other platinum complexing agents have anticancer effects with trade names Platinol and Paraplatin that treats signals of Eloxatine testicular, ovarian and colon cancers. These promising agents promotes vital cure for rare cancer diseases and can be found in list for clinical and medical uses.

            Most complexing agents are clinically used as therapeutic agents. Research has found out that these agents were commercially sold as prescribed drug by the doctor for chemotherapy sessions. These help relaxes pain from radiotherapy in which radioactive particles were emitted to deteriorate the cancer cells. But then, this type of treatment is dangerous to cancer patients in whom the patient suffers from hair loss, loss of appetite, vomiting, nausea, respiratory damages, and deterioration of tissue and muscle cells. The clinically used therapeutic agents are promising to cure such illness. Platinum complexes such as cisplatin, cis-[PtCl₂(NH₃)₂], also known as cis-DDP is one of the best known example of a small molecule metal-containing drug. Cisplatin is cited for treatment of germ-cell cancers, ovarian cancer, and small cell lung cancer, neck and esophageal cancers. Researchers O'Dwyer and Stevenson in their journal entitled, Cisplatin and Its Analogues:In Cancer Principles and Practice of Oncology, a typical dose ranges from 20 mg/m² to 100 mg/m² and treated for up to five consecutive days. The success of cisplatin has also its limited range. Side effects of cisplatin include close-limiting nephrotoxicity, neurotoxicity, ototoxicity, and emetogenesis. The cisplatin usually works with binding of DNA and developed a detailed structural cisplatin-DNA interaction. This interaction has downstream effects to the cell target of protein recognition and cell signalling events that ultimately caused of cancer cell death. Since then, the use of this promising drug evolved many metal complexes to be discovered.

            Nonplatinum anticancer agents are one of anticancer agents that are formally developed with the development of analogs of platinum compounds. These nonplatinum agents were studied extensively  similar to platinum metal complexes process. One example of nonplatinum complex is ruthenium complex or ruthenium ammine complex of the general compound, [RuCl_n(NH₃)_6-n]^z+ showed good activity as anticancer agents same as platinum agents used for curing germ-cell cancer. The main advantage of ruthenium ammine complexes which has been described by Clarke, M.J in his book, Progress in Clinical Biochemistry, 1989, Vol 10, is that these compounds have a rich DNA chemistry. Furthermore, the ruthenium, Ru(II) state enhances its DNA binding in which the guanine N7 is the preferred site of aqua species [Ru(H₂O)(NH₃)₅]²⁺ and metal migration occur to other nucleobases. A wide variety of Ru-based complexes exhibit anticancer activity in animals such as carboxylate-bridged di- and trinuclear complexes.

Other nonplatinum anticancer agent is arsenic trioxide. It is considered as one of most targeted approach in cancer chemotherapy with special emphasis in signalling pathways. Arsenic has been used therapeutically for more than thousands of years and was used formally in 1930's for treatment of chronic myelogenous leukemia. Chinese reports initially described the used of arsenic trioxide and was recently reported because of its efficacy and use. Treatment of dose as stated by Rust, D. M in Oncologist 2001, is about 0.15 mg kg^-1 d^-1 yet the side effects are fatal. The disadvantages for using arsenic trioxide are cardiotoxicity that possibly includes toxic arsenic blocks the passage of blood throughout the heart, skin rashes and hyperglycemia. The arsenic trioxide complex is remarkable which apparently affects intracellular signal transduction pathways and the mechanism of cancer cell death is multiple. The effects of arsenic trioxide may include as mitochondriotoxic anticancer agent. Mitochondria, one of the part of cell named as the "powerhouse" that produces ATP for energy cellular of cell is one of the main drive to cause a normal cell to be a cancerous cell. With the help of arsenic trioxide, membrane potential decreases and membrane permeability increases of mitochondria resulting in the release of messenger molecules for degradation of mutation of cancer cells.  Mitochondrial DNA is also an attractive target because it is significantly sensitive of covalent damage. This observation has evolved many treatment strategies in which differentiated between normal and tumor cells to selective tumor cell killing.

Recent advances demonstrate significant impact to medicine and biochemical application. The utilization of metal complexes as drugs presents a promising development of new drugs that possibly used as therapeutics and chemotherapy agents. The development of these metal complexes will be utilized for future advancement for increasing anticancer potency improvement. From platinum metal complexes that have been achieved on the mechanistic understanding of DNA binding to nonplatinum agent (i.e As₂O₃) that exhibits antitumor activity help us understand the importance of metal complexes.