Platinum compounds antitumor activity

Antitumor Activities of Platinum Compounds Against L1210 in Vivo... 

Figure 1.6 The antitumor active platinum compound ds-dichlorodiammineplatinum (II).

The greatest research effort on radiation sensitizers has focused on organic compounds however, platinum complexes conform to the hypotheses for radiation sensitizers since they are electron affinic and react preferentially with the hydrated electron in aqueous solution. Early studies of cisplatin in combination with radiation therapy suggested a synergistic effect in antitumor activity (50,51). Much of the initial data were obtained using cells in tissue culture (52), these data indicated that the potential of cisplatin to inhibit repair of radiation-induced damage to DNA could be an important contributor to the enhanced tumor cell killing seen in vivo by the combination of these two modes of treatment. 

In this section a brief summary of the most important Pt—DNA interactions, including cis-Pt, irans-Pt, and other related platinum compounds, and their relevance for antitumor activity will be presented. For more detailed information the reader is referred to the several reviews that have appeared on this subject during the last 5 years (49-53). 

The two classes of antitumor-active compounds [Pt(diam)(R R" S0)C1J(N03) (23) and [cis-PT(NH3)2(N-het)Cl]Cl(24) are in principle monofunctional platinum compounds (see also Section I and Fig. 3) and their antitumor activity cannot be simply explained by the formation of products such as 4 and 6 in Fig. 5, especially because other... 

The reaction of sulfur-containing biomolecules with platinum antitumor compounds, thereby preventing binding to the critical DNA target, is a possible mechanism of inactivation and is supported by numerous studies. Thus, glutathione (GSH, a cysteine-containing tripeptide see also Fig. 6), which is the predominant intracellular thiol and is present in concentrations varying from 0.5 to 10 mM, is able to inhibit the reaction of DNA with [Pt(en)Cl2] (74) and with cis-Pt (75, 76). It has also been observed that the presence of cysteine can inhibit the reaction between cis-Pt and d-Guo (77). Furthermore, the antitumor activity of cis-Pt was proved to be inhibited by coadministered methionine (78, 79) and even a bis-adduct between cis-Pt and methionine has been isolated from the urine of patients (80). 

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). 

Miscellaneous. Reduction of a palladium salt by CO is the basis of a visual test for ambient carbon monoxide (227). Palladium compounds are used as photographic sensitizers (228). The low dimensional mixed valence compound Csq 3[Pd(S2C2(CN)2)] 0.5H2O behaves as a semimetal at room temperature (229). Palladium compounds isostructural with potent platinum antitumor compounds have poor antitumor activity (230). 

In laboratory animals, parenteral administration of organic and inorganic selenium (210 to 12,000 ig/kg) has been shown to protect against cisplatin-induced nephrotoxicity. Protection occurs without apparent inhibition of the antineoplastic activity of cisplatin, although this may be attributed to the fact that selenium administration allows for higher doses of cisplatin to be used. Additionally, selenium administration reduces cisplatin-induced myelosuppression. This raises a concern similar to that with administering cisplatin with thiol compounds, i.e., that the reduction of myelosuppression may indicate that selenium can also interfere with the antitumor activity of cisplatin. Selenium, with chemical properties similar to those of sulfur, can bind with platinum and... 

Most platinum compounds exist as coordination complexes the tetravalent compounds typically are more toxic than the hexavalent ones [10]. Certain neutral platinum complexes exhibit antitumor activity and therefore are used in chemotherapy drugs such as cisplatin. Speeiation is required to distinguish platinum chemotherapy drugs from their metabolites in patients blood and serum samples. 

Ruiz J, Lorenzo J, Sanglas L, Cutillas N, Vicente C, Villa MD, Aviles FX, Lopez G, Moreno V, Perez J, Bautista D (2006) Palladium(II) and platinum(II) organometallic complexes with the model nucleobase anions of thymine, uracil, and cytosine antitumor activity and interactions with DNA of the platinum compounds. Inorg Chem 45 6347-6360... 

Ruiz J, Villa MD, Cutillas N, Lopez G, de Haro C, Bautista D, Moreno V, Valencia L (2008) Palladium(II) and Platinum(II) Organometallic Complexes with 4, 7-dihydro-5-methyl-7-oxo[l, 2, 4]triazolo[l, 5-a]pyrimidine. Antitumor activity of the platinum compounds. Inorg Chem 47 4490 1505... 

It is rather surprising, however, that, although much of the Pt2n chemistry has come about as result of the serendipitous discovery of the first platinum pyrimidine blue which proved to have high antitumor activity as well as low renal toxicity [1], research on anticancer activity of most of these Pt " compounds has not started until very recently [129]. 

Methods for Screening the Potential Antitumor Activity of Platinum Compounds in Combinatorial Libraries... 

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