Platinum compounds, toxicity

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

Caution. All zero-valent platinum compounds and trialkylphosphines employed here are extremely air sensitive and should be handled in a dry nitrogen or argon atmosphere. The trialkylphosphines are malodorous and toxic, and should be handled with care, in a well-ventilated hood. All solvents should be dried (except ethanolj and distilled under nitrogen. 

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. 

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of the parent compound cisplatin almost led to its abandonment, until Cvitkovic et al. introduced aggressive hydration, which prevented the development of acute renal failure [2] [3], As noted above, the toxicity of cisplatin was a driving force both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. 

In spite of much effort that has been put into reducing the side-effects, toxicity remains a major limitation of the clinical use of platinum complexes in anticancer therapy [26][27] [29] [30] and several compounds termed rescue agents , or protective agents have been investigated for co-administration with platinum compounds in order modulate these side effects of platinum therapy. 

Research in the last decade has made clear that the toxic side effects of platinum compounds have an exciting molecular basis. It has stimulated the research activities dealing with Pt compounds and rescue agents (usually S-donor ligands) and especially the study of the reactions of these compounds in combination with other cellular components and their complicated cell-wall transport. 

Following on from the success of carboplatin, there have been additional similar second-generation less toxic platinum compounds introduced into Phase-I trial. Generally, these have added little to the properties already provided by carboplatin although at least one (254-S, Nedaplatin in Japan) has now received limited marketing approval. However, to date carboplatin is the only second-generation analogue in widespread use. 

The discovery, ca. 1968, by B. Rosenberg, that the cis isomer has anti-tumor activity stimulated the synthesis and screening of over 2000 different types of complexes with different amines and anionic ligands. Platinum compounds are among the most effective medications for the treatment of advanced cancer PtCl2(NH3)2 ( Cisplatin ) is mainly used for the treatment of testicular and ovarian cancer. One of its drawbacks are the severe toxic side-effects which may be related to the facile hydrolysis of Cl ligands under physiological conditions ... 

PLATINUM COMPOUNDS AMINOGLYCOSIDES, CAPREOMYCIN, COLISTIN, STREPTOMYCIN, VANCOMYCIN t risk of renal toxicity and renal failure and of ototoxicity. The ototoxicity tends to occur when cisplatin is administered early during the course of aminoglycoside therapy Additive renal toxicity Monitor renal function prior to and during therapy, and ensure an intake of at least 2 L of fluid daily. Monitor serum potassium and magnesium and correct any deficiencies. Most side-effects of aminoglycosides are dose-related, and it is necessary to t interval between doses and 1 dose of aminoglycoside if there is impaired renal function... 

PLATINUM COMPOUNDS CICLOSPORIN t risk of renal toxicity and renal failure Additive renal toxicity Monitor renal function prior to and during therapy, and ensure an intake of at least 2 L of fluid daily. Monitor serum potassium and magnesium and correct any deficiencies... 

PLATINUM COMPOUNDS DIURETICS-LOOP t risk of auditory toxic effects with cisplatin Loop diuretics cause tinnitus and deafness as side-effects. Additive toxic effects on auditory system likely Monitor hearing (auditory function) regularly, particularly if patients report symptoms such as tinnitus or impaired hearing... 

After intravenous or oral administration of the drug, it undergoes several biotransformations that activate its toxicity (tumor cells as well as nephro- and neurotoxicity). A number of speciation studies that focused on characterization and quantification of parent drug and its possible metabohtes in vitro and in vivo have been reported. Element-specific ICP-MS detection has been applied after LC separation of platinum compounds. In Figure 6, the LC-ICP-MS chromatogram is presented, and this was obtained for the mixture of cancerostatic platinum compounds. ... 

OSH A PEL TWA 0.002 mg(Pt)/m3 ACGIH TLV TWA 0.002 mg(Pt)/m3 SAFETY PROFILE Poison by inhalation and ingestion. Human pulmonary system effects by inhalation. See also PLATINUM COMPOUNDS. An explosively unstable compound. Incompatible with KOH (boiling with alkah yields a product which, after drying, wiU explode 205° or if mixed with combustibles). When heated to decomposition it emits very toxic fumes of cr, NOx, and NH3. 

SAFETY PROFILE Poison by intraperitoneal route. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx. See also PLATINUM COMPOUNDS. 

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