Platinum nephrotoxicity

Dobyan DC, Levi J, Jacobs C, Kosek J, Weiner MW Mechanism of cis-platinum nephrotoxicity II. Morphologic observations. J.PharmacoI.Exp.Ther. 213 551 -556,1980... 

Borch RE, Pleasants ME. Inhibition of cis-platinum nephrotoxicity by diethyidithiocarbamate rescue in a rat renal model. Proc Natl Acad Sci USA 1979 76 6611-4. 

Levi J, Jacobs C, Kalman S, McTigue M, Weiner MWJ. Mechanism of cis-platinum nephrotoxicity I. Effectson sulfhydryl groups in rat kidneys. Pharmacol ExpTher 1980 213 545-50. 

The mechanism of platinum nephrotoxicity may be similar to that of mercury and may involve depletion of SH groups of the renal tubules and in this case the sulfur agents would act in competition with the renal SH groups [32]. The ATPase enzyme is critical for kidney function (see Chapter 12.1) and this has also been proposed as the site of action [33, 34], although it has been pointed out that the inhibiting concentrations are high and unlikely to be achieved in vivo [35]. Other urinary enzymes have also been examined for inhibition by platinum complexes [28, 36]. In general, the mechanisms of action related to the toxic manifestations of cisplatin are unclear, especially when compared to the details of the proposed Pt—DNA reaction (Chapter 4). 

DDTC can inhibit platinum nephrotoxicity without affecting activity (Chapter 2.2). In this case, studies with model compounds showed that the bis(guanosine) complexes were not affected by DDTC (10 mM, 37 C) whereas a mono(guanosine) complex and a bis(adenosine) complex reacted readily with the DDTC ligand [137]. These results confirm observations from studies on DNA, where very little platinum is removed by DDTC at low binding ratios, and allow the prediction that DDTC should not reverse the toxic lesion on DNA, as observed [137]. It would be interesting to correlate the various effects of the nephroprotective sulfur nucleophiles (Chapter 2.2) and their effects on antitumour activity of cisplatin with the behavior toward model compounds (see also Chapter 3.7). 

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],... 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

Ali, B.H. AI Moundhri, M.S. (2006). Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compoimds a review of some recent research. Food and Chemical Toxicology, Vol. 44, No.8, (August 2006), pp. 1173-1183, ISSN 0278-6915. 

Overall survival is affected by the success of the initial surgery to debulk the tumor to less than 1 cm of disease and response to first-line chemotherapy. The CA-125 level should be monitored with each cycle, and at least a 50% reduction in CA-125 after four cycles of taxane/platinum chemotherapy is related to an improved prognosis. Patients who achieve a complete response should have follow-up examinations every 3 months, including CA-125 determination, physical examination, pelvic examination, and appropriate diagnostic scans (e.g., CT scan, MRI, or PET scan) and should be evaluated for the detection of disease. Evaluate patients for resolution of any residual chemotherapy-related side effects, including neuropathies, nephrotoxicity, ototoxicity, myelosuppression, and nausea/vomiting. 

The second criteria, a different activity spectrum, is met by oxaliplatin (Figure 1.9A), the l isomer of [oxalatol f ra/rv-1,2-diaminocyclohexane)platinum (II)], oxaliplatin, [Pt(II)(oxalato)(DACH)]. This platinum agent is used for secondary treatment of metastatic colorectal cancer.77 Oxaliplatin, like carboplatin, has a kinetically slower leaving group, and is also less nephrotoxic than cisDDP. The limiting toxicity of oxaliplatin is peripheral sensory neuropathy, also seen with cisDDP. The neuropathy affects the extremities and increases in incidence and... 

The fourth criteria, that of oral administration, is being developed and evaluated for ZD0473 as just mentioned. Another candidate in this field, JM216, cis, trans, cw-[dichlorodiacetatoammine(cyclohexylamine)platinum(IV)] (see Figure 7.6D), is an orally active platinum(IV) drug being evaluated in clinical trials. This platinum (IV) complex has demonstrated activity in cisplatin-resistant tumors and exhibits less nephrotoxicity and neurotoxicity than does cisDDP. 

Many tremendous hopes, raised up in the past by the discovery of very powerful antitumor chemicals, vanished actually to some extent when it was shown that these drugs were not specific enough of the cancerizcd part of the body but were also attacking some other healthy organs in such a disastrous manner that the patient dies cured. . . This is the case, for example, with several platinum dru which induce nephrotoxicity (kidney damage), of nitrosoureas (bone marrow depletion) and of some alkaloids (heart diseases). 

Oxaliplatin is a newer platinum-based agent. It is most frequently administered in combination with fluorouracil and leucovorin for the treatment of colorectal cancer. Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin. 

The affinity of sulfur for platinum complexes has led to investigations of numerous sulfur nucleophiles as inhibitors of cis-Pt nephrotoxicity, including Naddtc, STS, WR-2721, mesna, methionine, thiourea, cysteine, IV-acetylcysteine, penicillamine, and GSH. Of these, Naddtc, STS, and WR-2721 are undergoing preclinical and/or clinical evaluation (Fig. 8). Some of the more promising compounds will be discussed here. 

Thiourea probably acts in a manner comparable to that of Naddtc and should also be administered after cis-Pt treatment (78). Like Naddtc, thiourea is able to remove platinum from platinated enzymes, such as leucine aminopeptidase (76, 128), y-glutamyltranspeptidase (76,128), and fumarase (129) (Fig. 9), and from Pt-methionine model adducts (Table III) (131). However, thiourea appears to be less useful as an inhibitor of nephrotoxicity it also reacts quite rapidly with platinum-DNA cross-links (56). 

The development of permanent nephrotoxicity. Nephrotoxicity cannot be cured by Naddtc and thiourea when administered more than 4 hours after cis-Pt treatment. A possible mechanism for the development of permanent nephrotoxicity might be that the platinum migrates from a methionine to a cysteine within a protein, resulting in irreversible binding. 

Carboplatin is a promising second-generation platinum agent. Because it is less reactive, it causes less nephrotoxicity, myelosuppression, and thrombocytopenia. 

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... 

Os-platinum (cisplatin) binds to intracellular DNA, causing both interstrand and intrastrand cross-linking. It is a cell-cycle phase nonspecific agent. Os-platinum, which is ineffective orally, is used for testicular, bladder, and head and neck cancers. It precipitates nephrotoxicity, ototoxicity, and gastrointestinal injury. 

The platinum complexes appear to synergize with certain other anticancer drugs. Aggressive hydration with intravenous saline infusion alone or with saline and mannitol or other diuretics appears to significantly reduce the incidence of nephrotoxicity. 

Of the platinum-based drugs, cisplatin or cf -diarnmincdichloroplatinum (II) has been the most studied in treatments of cancerous tumours. Quantities of the drug administered in treatments must be carefully controlled because of appearances of side effects, primarily nephrotoxicity and nausea in patients. In some studies, ultrafilterable cisplatin, or free platinum in blood serum or plasma has been differentiated from platinum bound to proteins (Goel et al., 1990). HPLC has been used extensively in separations of intact cisplatin from other species. An anion-exchange column was connected to a post-column reactor and a UV-spectrophotometer for measurements of cisplatin concentrations in plasma and urine (Kizu et al., 1995). The detection limit was 20 nmol dm-3. Modes of action... 

---