Platinum Administration Research Articles

Interaction of platinum with metallothionein-like ligands in the rat kidney after administration of cis-dichlorodiammine platinum II

After the administration of the anticancer drug cis-dichlorodiammine platinum II (cisplatin) to male rats, the Pt in the soluble fraction of the kidney is isolated, by gel filtration, in association with a high molecular weight component and a low molecular weight fraction. At 24 h, Pt is also recovered in a metallothionein-like fraction which elutes from Sephadex G-50 with a lower apparent molecular weight than endogenous (Cu, Zn)-thionein or Cd-thionein isolated from the kidneys of Cd 2+-treated rats. None of these low molecular weight metal-binding fractions binds to Octyl Sepharose CL-4B. On DE-52 ion exchange chromatography, Cd-thionein is resolved into two isometallothioneins whereas the low molecular weight Pt-binding fraction is only partially purified and contains at least six components which elute at higher gradient concentrations than metallothionein. Pretreatment with Cd 2+ which stimulates the synthesis of renal and hepatic metallothionein has no effect on the uptake and subcellular distribution of Pt in the liver and kidneys. Cisplatin treatment reduces the concentration of Cu and Zn in the renal metallothionein and other soluble protein fractions in the kidney. When administered to Cd 2+-pretreated rats, cisplatin promotes the loss of Zn from the soluble protein fractions but causes the redistribution of Cd from the metallothionein to the high molecular weight fraction and fails to inhibit the Cd 2+-induced accumulation of Cu in the kidneys and the binding of Cu to the soluble protein fractions. It is suggested that metallothionein probably does not have a significant role in the renal metabolism of Pt following the administration of cisplatin to rats.

Phase II clinical trial of cis-dichlorodiammine platinum (cis-DDP) for antitumorigenic activity in previously untreated patients with metastatic breast cancer.

A phase II clinical trial was set up in metastatic breast cancer patients who had not received previous cytotoxic drug therapy, involving the administration of cis-dichlorodiammine platinum (cis-DDP). Patients aged up to 75 years and with pathohistologically confirmed disease were entered on the trial. All patients had measurable disease, a performance status (Karnofsky) of greater than 40, and an expected survival of greater than 6 weeks. In all 38 patients entered the trial, and 35 have been evaluated. The predominating metastatic sites included soft tissues (19), visceral organs (12), and bones (7 patients). cis-DDP was administered in a daily dose of 30 mg/m2 IV by a 4-h drip for 4 days, with customary hyperhydration. The results indicate a pronounced antitumorigenic effect of cis-DDP and a response rate of 54% (19/35), with 13 complete remissions (37%) and six partial remissions (17%). In terms of site the best response was obtained in soft-tissue processes (13/19; 68%), followed by visceral organs (4/10; 40%); the response rate was lowest in bones (2/6; 33%). The menopausal status and prior hormone therapy did not essentially influence the results of treatment, unlike previous irradiation. Patients with a lower performance status (40-70) had a significantly lower response rate (36% vs 63%; P less than 0.05). Toxic side-effects were moderate and did not substantially affect the general condition of the patients. A transient increase of serum creatinine was observed in 4 patients, and neurotoxicity in 2 patients. The results of the trial warrant the conclusion that cis-DDP has a pronounced antitumorigenic effect in untreated metastatic breast cancer, particularly in soft-tissue metastases. These results call for additional clinical study of the cytotoxic effect of cis-DDP in untreated metastatic breast cancer.

Neonatal respiratory distress in the presence of amniotic fluid phosphatidylglycerol

Stage I Sertoli-Leydig cell tumors which carry a high risk of recurrent disease, such as undifferentiated tumors, tumors with high mitotic counts, and possibly hormonally active tumors. The toxicity from the suggested protocol has been tolerable in the 10 patients treated with two to eight courses of BV-CAP chemotherapy in our institution and has been characterized by hypomagnesemia, nausea during c&platinum administration, reversible alopecia, and grade I hematologic toxicity predominantly of the red blood cell line. Renal toxicity, peripheral paresthesias, and ototoxicity were not observed in the present case.

Effect of ultrasound-induced hyperthermia and cis-diamminedichloride platinum II on murine renal function.

Murine renal function was evaluated after ultrasound-induced kidney hyperthermia (42.5 degrees C and 46.5 degrees C for 35 minutes) and the administration of cis-diamminedichloride platinum II (8 mg/kg). A quantitative immunonephelometric technique was employed to determine urinary total protein (TP) and albumin (Alb) 1-180 days post-treatment. Hyperthermia of 46.5 degrees C elevated urinary TP excretion significantly more than that of 42.5 degrees C cis-diamminedichloride platinum (Cis DDP) administration greatly increase urine TP with a peak mean TP concentration of 488 microgram/ml, four days after Cis DDP (normal range was 26-48 microgram/ml). This returned to normal by day 14. The TP excretion after 42.5 degrees C hyperthermia with concurrent Cis DDP was similar to Cis DDP alone, implying there was no potentiation of early or late Cis-DDP-induced renal damage by hyperthermia. Late mouse mortality was greater (P = 0.08) after Cis DDP alone, than Cis DDP with 42.5 degrees C hyperthermia. There was a statistically significant increase (P less than 0.05) in the Alb/TP excretion ratio after the addition of 42.5 degrees C hyperthermia to Cis DDP, implying an alteration in the site or nature of the Cis DDP renal lesion by hyperthermia.

Renal toxicity studies of protein-bound platinum(cis)

Incubation of dialyzed rat serum with cisplatin at a concentration of 908 ppm results in binding of platinum to the proteins and electrophoretic evidence of protein alterations. Intravenous administration of protein-bound platinum(cis), containing the same platinum content as an 8.5-mg/kg dose of cisplatin, fails to produce elevated serum BUN and creatinine levels as do equivalent doses of ‘free’ cisplatin in 0.9% saline. Light microscopy of the right side kidneys of rats receiving protein-bound platinum(cis) revealed no obvious pathology while the kidneys of rats receiving ‘free’ cisplatin showed consistent pathological alterations including hydropic degeneration and pyknotic nuclei. These observations suggest that a protein-bound form of platinum will be unlikely to contribute to the renal toxicity observed during cisplatin chemotherapy.