Titanium Anticancer Drugs

After the discovery of the tumor-inhibiting properties of cis-diammine dichloro-platinum(II) (cisplatin) in 196912 and its routine use as a leading cytostatic drug since 1979,13 there has been increasing interest in the development of new anti-tumor metal agents including non-platinum metal complexes. Among these, two monomeric titanium(IV) complexes have qualified for clinical trials (Figure 7.1): [TiIV(bzac)2(OEt)2] (budotitane) and [Cp2TiIVCl2] (titanocene dichloride).

Relevant reviews on titanium complexes in cancer treatment have been given by Kopf-Maier and Kopf,14 17 Keppler etal.,18 21 Harding and Mokdsi,22 Caruso, Rossi and Pettinari 4 and Melendez.23

Most anti-tumor agents act by interfering with molecular processes in the cell replication cycle.4,13 Cisplatin is well known as a DNA-damaging agent. It is generally believed that cisplatin arrives at the tumor cell intact, crosses the plasma cell membrane to areas of low concentration of Cl— ions (extracellular [Cl—] is 100 mM and intracellular [Cl—] is 3mM). It then undergoes hydrolysis with H2O and/or OH— groups replacing one or both of the Cl— anions. These new complexes become active, and subsequent intra- or inter-strand Pt DNA bonds, mainly involving guanine N(7) sites, are formed. Cisplatin then causes cells to arrest at either the G1-, S- or G2-phase of the cell cycle. Failing adequate repair, the cells eventually undergo an aberrant mitosis followed by

: Ti2(bzac)4Cl2O

: Ti2(bzac)4Cl2O

IV: Cp4Ti2Cl2O

Figure 7.1 Structural formula of the anti-tumor titanium complexes [TiIV(bzac)2(OEt)2] (budotitane, I, cis-cis-cis configuration shown) and [Cp2TiIVCl2] (titanocene dichloride, II) and of their possible dimeric hydrolysis products [TiIV2(bzac)4Cl2O] (III) and [Cp4TiIV2Cl2O] (IV)

apoptosis. A key question in view of such a mechanism is, why does cisplatin reach guanine-N(7) with competing S-donor ligands as glutathione or methionine available in the blood and in the cell?24

A reaction mechanism analogous to that of cisplatin may be suggested for the anti-cancer compounds budotitane and titanocene dichloride, since interaction with DNA has been described for both drugs.16,17 In a study of the intracellular localization of titanium in xenografted human adenocarcinomas of the colon after application of a single therapeutic dose (80 mg/m2) of titanocene dichloride in athymic mice,25 titanium was first detected in the nuclear chromatin 12 h after application. Titanium location was near phosphorus-rich areas, suggesting titan-ium-DNA interactions. In addition, cisplatin and the two titanium drugs have two labile groups in the cis position (chloride or ethoxy) as a common structural feature. This gives rise to initial speculation that the three drugs might have similar biological mechanisms. However, their spectrum of action is very different. Cisplatin is active against fast-growing tumors and can be used to cure testicular cancer. In addition, it is successfully used in ovarian, neck, lung and other cancers. The main targets of budotitane, in contrast, are gastrointestinal tumors, indicating a use against slow-growing cancers, which pose the biggest problem in cancer therapy today. Titanocene dichloride also has a spectrum of activity which is different from that of cisplatin. It showed activity against human adenocarcinomas of the stomach and colon which are insensitive to common cytostatic agents. In addition, several crystallographic studies indicate that in Cp2TiIVCl2 the Cp groups sterically prevent cross-linking DNA, and 31P NMR studies indicate a prevalence of Ti(IV) binding to phosphate oxygen.26 Therefore, titanocene dichloride seems not to function by analogy to cisplatin.

In contrast to the well-characterized platinum anti-cancer drugs, the active species for the anti-cancer activity of the titanium complexes in vivo has not yet been identified, and the mechanism including irreparable DNA damage and/or structural modification of DNA or other cellular targets is poorly understood.22

The actual ambiguity concerning the mechanism of action of titanium anticancer drugs has been summarized by Guo and Sadler.27 Metal anti-cancer complexes are often electrophilic and can react with many biomolecules, including amino acids, polyphosphates, proteins and nucleic acids. However, these biomolecules may be located in different extra- or intra-cellular compartments. Therefore, carrier molecules (e.g. proteins such as albumin and transferrin, or small molecules such as ATP, glutathione or citrate) may be used to communicate between the compartments. Indeed, a detailed recent study has confirmed the uptake of Ti(IV) from Cp2TiIVCl2 by human transferrin at blood plasma pH values, release of bound Ti(IV) to ATP at cellular endosomal pH values, and replacement of Ti(IV) by Fe(III), as well as uptake of a Ti2-human-transferrin complex into placental cancer cells.28 The substrate binding properties are controlled by natural gradients of e.g. pH, ATP or by ionic gradients. The gradients could also alter the affinity of drug molecules for different cellular components and facilitate drug binding to its target. The hard Lewis acid Ti(IV) finally may be transported into the cell by transferrins, iron-binding single-chain glycopro-teins containing approximately 700 amino acids with molecular masses of about 80 kDa, which offer distorted octahedral coordination sites for metal ions involving oxygen and nitrogen donors.29 Titanium(IV) then may bind to DNA at both negatively charged phosphates on the backbone and base nitrogen donors.30 The high DNA concentration in the cell nucleus and potentially low pH close to the surface of DNA may favor DNA as a target for Ti(lV) binding under these conditions, since Ti(IV) does not strongly bind to DNA bases at physiological pH, but forms strong complexes with nucleotides only at pH values below 5.27

Discussing possible reaction mechanisms of the two clinically tested titanium drugs, an interesting aspect has to be taken into account. Given the hydrolytic instability of budotitane and of titanocene dichloride at physiological conditions, hydrolytic decomposition products should also be considered as possible active species. For example, the dimeric complex [TiIV2(bzac)4Cl2O], m-oxo-dichlorotetrakis(l-phenylbutane-l,3-dionato)dititanium(IV) (Figure 7.1, III) may be formed already during the storage of budotitane and shows good anti-tumor activity. Polynuclear species such as [Cp4TiIV2Cl2O] (Figure 7.1, IV), which are typical hydrolysis products of titanocene dichloride and precursors to the insoluble polymer [(CpTiIVO)4O2]n, have also shown reduced or sporadic anti-tumor activity in animal studies.l5,22

In addition to the two Ti(IV) anti-tumor drugs described above, a third Ti(IV) compound deserves a special comment TiO2 exhibits anti-tumor activity when finely dispersed and activated photochemically.4 The effect may be described as photokilling of malignant cells by TiO2 powder (photodynamic cancer therapy). For example, in a study using TiO2 particles with UV irradiation, the photoexcited TiO2 particles significantly suppressed the growth of HeLa cells that were implanted in nude mice.31 The killing effect of photo-excited ultrafine TiO2 particles has also been studied using U937 cells.32 The electrophorogram shows that reactive oxygen species produced by photoex-cited TiO2 can damage DNA, which results in cell death. In this context, it is interesting to note that TiO2 is also the final stage of budotitane hydrolysis.18 Therefore, a new strategy could imply first bringing a titanium drug to the tumor (Ti(IV) tends to concentrate in DNA regions of the cell) and inducing titanium hydrolysis to generate TiO2. Then, by using tumor imaging, a well-focused beam of light could be applied. Since the radiation needed for TiO2 activation is much less energetic than X-rays, less damage to the surrounding normal tissue would be expected.4

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