Platinum toxicity

Dedon and coworkers (1986) observed the possible protective action of thionrea against platinum toxicity. Thiourea and other sulfur-containing nncleophiles have the ability to chelate and remove platinum from biochemical sites of toxicity. 

Some metals used as metallic coatings are considered nontoxic, such as aluminum, magnesium, iron, tin, indium, molybdenum, tungsten, titanium, tantalum, niobium, bismuth, and the precious metals such as gold, platinum, rhodium, and palladium. However, some of the most important poUutants are metallic contaminants of these metals. Metals that can be bioconcentrated to harmful levels, especially in predators at the top of the food chain, such as mercury, cadmium, and lead are especially problematic. Other metals such as silver, copper, nickel, zinc, and chromium in the hexavalent oxidation state are highly toxic to aquatic Hfe (37,57—60). 

Some elements found in body tissues have no apparent physiological role, but have not been shown to be toxic. Examples are mbidium, strontium, titanium, niobium, germanium, and lanthanum. Other elements are toxic when found in greater than trace amounts, and sometimes in trace amounts. These latter elements include arsenic, mercury, lead, cadmium, silver, zirconium, beryUium, and thallium. Numerous other elements are used in medicine in nonnutrient roles. These include lithium, bismuth, antimony, bromine, platinum, and gold (Eig. 1). The interactions of mineral nutrients with... 

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Hydrofluoric acid [7664-39-3] M 20.0, b 112.2"(aq azeotrope, 38.2% HF), d 1.15 (47-53% HF), pK 3.21. Freed from lead (Pb ca 0.002ppm) by co-precipitation with Srp2, by addition of lOmL of 10% SrCl2 soln per kilogram of the cone acid. After the ppte has settled, the supernatant is decanted through a filter in a hard-rubber or paraffin lined-glass vessel [Rosenqvist Am J Sci 240 358 1942. Pure aqueous HF solutions (up to 25M) can be prepared by isothermal distn in polyethylene, polypropylene or platinum apparatus [Kwestroo and Visser Analyst 90 297 7965]. HIGHLY TOXIC. 

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a ds complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclo-butanedicarboxylic acid to yield carboplatin [23],... 

Palladium(II) complexes with these features are inactive, owing to their greater lability. Platinum(IV) complexes are often less toxic than their platinum(II) analogues, because of their stability to substitution, though it is believed that they undergo in vivo reduction to platinum(II). 

The most successful class of active ingredient for both oxidation and reduction is that of the noble metals silver, gold, ruthenium, rhodium, palladium, osmium, iridium, and platinum. Platinum and palladium readily oxidize carbon monoxide, all the hydrocarbons except methane, and the partially oxygenated organic compounds such as aldehydes and alcohols. Under reducing conditions, platinum can convert NO to N2 and to NH3. Platinum and palladium are used in small quantities as promoters for less active base metal oxide catalysts. Platinum is also a candidate for simultaneous oxidation and reduction when the oxidant/re-ductant ratio is within 1% of stoichiometry. The other four elements of the platinum family are in short supply. Ruthenium produces the least NH3 concentration in NO reduction in comparison with other catalysts, but it forms volatile toxic oxides. 

Perez-Soler, R., Khokhar, A. R., Hacker, M. P., and Lopez-Berestein, G. (1986). Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles. Cancer Res., 46. 6269-6273. 

Doublet chemotherapy regimens are superior in response to single-agent regimens and should be used when the patient can tolerate the associated toxicity. Platinum-containing doublets are first-line treatment in most cases. 

Since the efficacy of the agents is similar, selection of an agent for the treatment of recurrent platinum-resistant ovarian cancer depends on residual toxicities, physician preference, and patient convenience. 

Peroxides are very toxic to the cornea of the eye. After the disinfection cycle, and before placing the lens in the eye, hydrogen peroxide must be completely neutralized by reducing agents, catalase, or transition metals, such as platinum. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

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