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At least 19 recordsLinked to original sources
PubMed1988

Inhibition of lactate-dehydrogenase by cisplatin and other platinum-compounds: enzyme leakage of LDH is not a suitable method to measure platinum-compound-induced kidney cell damage in vitro.

The effects of three platinum-compounds on the activity of hog muscle lactate-dehydrogenase (LDH), cytosolic LDH released from rat renal cortical slices and cytosolic LDH isolated from rat kidney cells were investigated. In vitro, cisplatin inhibited the activity of LDH in a concentration-dependent manner. At a concentration of 0.25 mg/ml, cisplatin, transplatin and cisplatin-hydrolysis-products inhibited the activity of LDH time-dependently. These observations make it doubtful to use LDH-enzyme leakage experiments to demonstrate damage of kidney cells by platinum-compounds. The nonnephrotoxic compound transplatin had an enhanced inhibitory effect on the activity of LDH compared to the nephrotoxic compounds cisplatin or cisplatin-hydrolysis-products (transplatin greater than cisplatin greater than cisplatin-hydrolysis-products). Thus, LDH-enzyme inhibition seems not to be related to the nephrotoxicity of cisplatin.

Animals↗
PubMed1995

Platinum concentrations in uterus and serum after internal iliac arterial infusion of platinum compounds in rabbits.

OBJECTIVE: To compare three platinum compounds, and study the pharmacokinetics of these compounds after systemic and intra-arterial infusion. METHODS: Adult female rabbits received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cisdiammine(glycolato)platinum (254-S) via the internal iliac artery or jugular vein. The doses were equitoxic. Platinum tissue concentration in uterus and platinum serum levels were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: Platinum uterine concentration after intra-arterial infusion was significantly higher than that after i.v. infusion for each drug (P < .05). The ratios of platinum uterine concentration after intra-arterial infusion to those after i.v. infusion were 2.24 for cisplatin, 1.83 for carboplatin, and 1.67 for 254-S measured 20 minutes after drug administration. The area under the curve of filtrated platinum (micrograms/mL.hours) was significantly lower for cisplatin compared with carboplatin and 254-S in both infusion methods (1.5 for cisplatin, 32.1 for carboplatin, and 16.0 for 254-S after i.v. administration, and 0.8, 30.9, and 15.2 after intra-arterial administration, respectively). CONCLUSION: Cisplatin produced the highest ratio of uterine to serum concentration of platinum after intra-arterial infusion.

Animals↗
PubMed1983

Sister chromatid exchanges induced by two radiosensitizing platinum compounds (cis-dichloro-bis isopropylamine trans dihydroxy platinum IV (CHIP) and cis platinum metronidazole2Cl2(FLAP)) in CHO cells in vitro.

Sister chromatid exchange (SCE) induction by two radiosensitizing platinum compounds (cis-dichloro-bis isopropylamine trans dihydroxy platinum IV (CHIP) and cis-platinum metronidazole2 Cl2 (FLAP] was studied in CHO cells in vitro. Both drugs induced SCE in a dose dependent manner. CHIP was a much more potent inducer of SCE than FLAP and produced almost 4 times as many SCE as FLAP at equimolar concentrations and twice as many at equitoxic dosage. Induction of SCE by a component of the FLAP molecule--metronidazole--was also examined. It did not cause any increase of SCE frequency over the control level when applied at 10 times the highest concentration of FLAP which was used.

Animals↗
PubMedDate not supplied

Chemotherapy of advanced L1210 leukemia with platinum compounds in combination with other antitumor agents.

Six antitumor platinum compounds were used in combination with cyclophosphamide (CY) plus one of five other antitumor drugs in the treatment of advanced (Day 3) L1210 leukemia in (C57BL/6 X DBA/2)F1 mice. The combination of CY with a platinum compound yielded a collective cure rate of 24%; the addition of a third drug to the dual regimen increased the collective cure rate to 55%. The most effective drugs when used in combination with platinum compounds plus CY were, in increasing order of efficacy, 5-fluorouracil, hydroxyurea, and methotrexate. No toxic deaths occurred with any regimen at the dose levels used.

Animals↗
PubMed1976

Combination chemotherapy of L1210 leukemia with platinum compounds and cyclophosphamide plus other selected antineoplastic agents.

Six antitumor platinum compounds were used in combination with cyclophosphamide plut 1 of 7 other antitumor drugs for treatment of L1210 leukemia in B6D2F [C57BL/6 X DMA/2) F] mice. Data obtained from each three-agent regimen were compared with those obtained after administration of each compound alone and each appropriate two-agent combination. No cure (greater than 60-day survival) was obtained with any compound used alone. Combination of cyclophosphamide with a platinum compound (Pt+CY) yielded a collective cure rate of 193/420, and the addition of a third cure rate to 290/420 (P less than 0.001). Certain regimens produced 100% cure rates. The most effective drugs when used in combination with PT+CY were cytosine arabinoside, 5-fluorouracil, hydroxyurea, and Yoshi-864. Adriamycin, methotrexate, and vincristine were less effective at the doses used. Toxicity, as evidenced by maximum weight loss, was slightly greater with the three-agent combinations than with the Pt+CY regimens.

Animals↗
PubMed1985

Microscale syntheses of anti-tumour platinum compounds labelled with 191Pt.

Several compounds of platinum have been found to have significant anti-tumour activity and are in various stages of clinical trials. Four such compounds: cis-PtCl2(NH3)2, cis PtCl2(cyclopropylamine)2, cis,trans-PtCl2(OH)2(isopropylamine)2 and cis-Pt(1,1-cyclobutanedicarboxylate) (NH3)2 were synthesised with radioactive platinum-191 as a label for the study of animal organ distribution, patient blood clearance, urinary excretion and renal uptake and clearance. This paper describes the microscale synthesis of these compounds. Purification and quality control procedures are also described.

Antineoplastic Agents↗
PubMed1997

Antitumor effects of internal iliac arterial infusion of platinum compounds in a rabbit cervical cancer model.

OBJECTIVE: To compare three platinum compounds for their antitumor effects on cervical cancer after systemic and intra-arterial infusion. METHODS: Adult female rabbits with squamous cell carcinoma of the uterine cervix received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cis-diammine (glycolato)platinum (254-S) via the internal iliac artery or ear vein. Platinum concentrations in the tumor and tumor size were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: The platinum concentration in the tumor after intra-arterial infusion was significantly higher than that after i.v. infusion for cisplatin. However, the tumor concentrations of platinum for carboplatin and 254-S did not differ between the infusion methods. The platinum concentration 20 minutes after i.v. infusion was significantly higher for 254-S than for cisplatin or carboplatin. The platinum concentration 7 days after intra-arterial infusion was significantly higher with cisplatin than with carboplatin or 254-S. Tumor size 7 days after intra-arterial infusion was significantly smaller than that after i.v. infusion for cisplatin (1.85 +/- 0.54 versus 5.60 +/- 2.60 cm2; P < .05). Tumor size was significantly smaller with 254-S than with cisplatin or carboplatin using the i.v. infusion method (2.40 +/- 0.21 cm2 for 254-S, 5.60 +/- 2.60 cm2 for cisplatin, and 5.13 +/- 1.59 cm2 for carboplatin, P < .05. CONCLUSIONS: Intra-arterial infusion seems to be a suitable route of administration for cisplatin, whereas i.v. infusion appears to have an advantage for 254-S in the treatment of cervical cancer.

Animals↗
PubMed1998

Predicting chemotherapeutic response to small-cell lung cancer of platinum compounds by thallium-201 single-photon emission computerized tomography.

Thallium-201 single-photon emission computerized tomography (SPECT) was used to clarify the relationship between 201Tl uptake and the response in chemotherapy to platinum compounds in 21 patients with small-cell lung cancer. 201Tl-SPECT scans were obtained twice: at 15 min (early scan) and 120 min (delayed scan) after an intravenous injection of 111 MBq (3 mCi) of thallium-201 chloride. We obtained the uptake ratio from each scan and calculated the retention index:uptake ratio = region of interest uptake/contralateral normal lung uptake; retention index = (delayed ratio - early ratio)/early ratio. After 201Tl scintigraphy, 12 patients received chemotherapy consisting of platinum compounds and nine were treated with chemoradiation. Among patients receiving only chemotherapy, the retention index correlated with the responses to chemotherapy. In an in vitro study, ouabain, an inhibitor of the Na,K-ATPase pump, reduced sensitivity to cisplatin and inhibited intracellular thallium uptake in the small-cell lung cancer cell line. These studies suggest that 201Tl-SPECT is a useful indicator of response to chemotherapy with platinum compounds in small-cell lung cancer, and that Na,K-ATPase is commonly involved in transporting both thallium and platinum compounds into cancer cells.

Aged↗
PubMedDate not supplied

[Comparative study of the action of antineoplastic platinum compounds with varying nephrotoxic effects].

Studying the action of the two antitumour platinum compounds--cisplatin capable of exerting a nephrotoxic action and cycloplatam which has no damaging effect on the kidney, it was found that 3 h after the administration of cycloplatam the content of platinum in the kidney was 2 times lower than in the cfse of cisplatin. Due to different dynamics of the excretion of platinum compounds from the kidney 5 lays after their addition the content of platinum in the kidney was the same in both cases. The content of platinum in the nuclei, mitochondria and supernatant with respect to a total content in the kidney cortex was almost equal for both compounds. Inhibition of nephrotoxic effect of cisplatin after the animals were pretreated with choline chloride or paraaminohippurate is not connected with a decrease of platinum in the kidney either 3 h, or 5 days after the injection of these preparations. The mechanisms of nephrotoxic action of cisplatin and its prevention are discussed.

Animals↗
PubMed1990

Nephrotoxicity of a new platinum compound, 254-S, evaluated with rat kidney cortical slices.

The addition of a new compound containing platinum, 254-S, an antineoplastic agent, to medium had no effect on p-aminohippurate (PAH) accumulation, gluconeogenesis, or potassium and ATP concentrations in rat kidney cortical slices at the concentrations tested, up to 10 mM. At 1 mM, cisplatin, used for comparison, significantly decreased all of these biochemical indices in the slices. Administration of 254-S at a low dose (10 mg/kg i.v.) to rats decreased the ability of the slices to accumulate PAH and to maintain the potassium concentration, without affecting levels of urea or creatinine in blood plasma. 254-S at a high dose (20 mg/kg i.v.) or cisplatin at 5 mg/kg (i.v.) also decreased these indices in the slices, and affected urea and creatinine in blood plasma. These results suggested that use of the renal slice technique gives data useful for the evaluation of the nephrotoxicity of 254-S, and that PAH accumulation and the potassium concentration in slices from rats treated with 254-S are indicators of nephrotoxic damage.

Adenosine Triphosphate↗
PubMed1991

[Antitumor activity and toxicity of KB-5424 R, a newly developed antitumor platinum compound].

KB-5424 (ab-(3-aminopyrrolidine)-cd-[glycolato (2-)-0, 0'] platinum (II) is a newly developed antitumor platinum compound which was synthesized at Kanebo Institute for Cancer Research. When the antitumor activity of KB-5424 was evaluated using several rodent tumors, no significant differences were observed between the antitumor activities of KB-5424, cisplatin (CDDP) and DWA-2114 R (DWA). KB-5424 was divided into two kinds of optical isomers, KB-5424 R and KB-5424 S, of which antitumor activity was compared each other. The maximum increased life span (ILSmax) on L 1210 of KB-5424 R was almost equal to that of CDDP and better than those of KB-5424 S and carboplatin (CBDCA). The antitumor activity of KB-5424 R on a human tumor xenograft MX-1 was almost identical to those of CDDP and CBDCA and better than that of DWA. Since the nephrotoxicity of KB-5424 R was significantly reduced comparing with CDDP, this newly developed antitumor platinum compound was thought to be a promising agent for the clinical application.

Animals↗
PubMedDate not supplied

Platinum compounds as radiosensitizers in strontium-89 metabolic radiotherapy.

PURPOSE: Strontium-89 is currently used for the treatment of painful bone metastases. This study reports on two preliminary experiences with low-dose platinum compounds, carboplatin and cisplatin, as radiosensitizers in 89Sr therapy. PATIENTS AND METHODS: 30 patients entered the carboplatin study: 15 patients (Group A) were treated with 148 MBq 89Sr followed by carboplatin (100 mg/m2 at 7 and 21 days) and 15 patients (Group B) were treated with 89Sr alone. 12 patients entered the cisplatin study: six patients (Arm 1) received 148 Mq 89Sr plus cisplatin (50 mg/m2) in two administrations (immediately before and 10 days after 89Sr injection) and six patients (Arm 2) received 89Sr plus two placebo administrations. Pain response was assessed 8 weeks after the therapy on the Wisconsin score modifications. RESULTS: No clinically significant adverse effects or myelosuppression by platinum compounds were observed. In carboplatin study a pain response was observed in 20 of 27 (74%) evaluable patients, 13/15 in group A and 7/12 in group B. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). In cisplatin study a pain response was observed in 10 of 12 (83%) evaluable patients, 5/6 in Arm 1 and 4/6 in Arm 2. CONCLUSIONS: Low-dose platinum compounds seem to enhance the effects of 89Sr radioisotope therapy on pain from bone metastases without relevant hematological toxicity.

Bone Neoplasms↗
PubMed1991

The effect of some platinum compounds on the activity of the CTP synthetase of Ehrlich ascites tumor cells: in vitro and in vivo studies.

The present work investigates the effect of cis-DDP (DDP, diamminedichloroplatinum(II)), trans-DDP, SPC (spermine platinum(II) complex), and K2PtCl4 on the activity of the CTP synthetase in the cytosol of Ehrlich ascites tumor cells. To study their in vitro effect, the platinum compounds were supplemented to the incubation mixture for the enzyme assay. A concentration dependent inhibition of the CTP synthetase was found which was strongest in the case of trans-DDP. When ascites cells collected from mice, pretreated in vivo with platinum compounds, were used, the enzyme assay showed that the inhibition is strongest in the case of cis-DDP and K2PtCl4 (about 90% inhibition). This distinct inhibitory effect of the platinum compounds in the present experiments may be explained with the metabolic conversions of the compounds in the organism to their more active forms and/or with the inhibition of the protein biosynthesis under their influence because the lifetime of the CTP synthetase is short. This last assertion is proved in this work by control experiments with the antibiotic cycloheximide, which is an inhibitor of the protein biosynthesis.

Animals↗
PubMed1979

Effect of platinum compounds on murine lymphocyte mitogenesis.

Polyclonal activation of T and B lymphocytes by concanavalin A and lipopolysaccharide mitogens, respectively, was used to study the effect of iv injection of the following platinum compounds: cis-dichlorodiammine platinum, dichloro 1,2 benzenediamine N,N' platinum, cis-dichlorobis(cyclohexylamine) platinum, and cis-dichlorobis(cyclopentylamine) platinum, on murine T and B splenic lymphocytes. The results indicated that platinum compounds were more toxic to T-lymphocyte function than to B-lymphocyte function. These results were from both single-dose-time-course analysis and dose-response studies.

Animals↗
PubMed1980

Criteria for the selection of second-generation platinum compounds.

Our selection of a potential second-generation platinum compound began with an initial short list of 8 compounds selected on the basis of antitumour and toxicity studies in mice. We now report further, more detailed investigations of the renal toxicity and antitumour activity of one of these compounds, cis-dichloro trans-dihydroxy bis isopropylamine platinum (IV) (CHIP), in comparison with cis-dichloro diammine platinum (II) (Neoplatin). CHIP was a more effective anti-tumour agent against both alkylating-agent sensitive and resistant strains of the Yoshida sarcoma (YSS and YSR respectively) than was Neoplatin. In addition CHIP produced negligible kidney toxicity as measured by blood urea levels. We have also compared the effects of these two drugs on nuclear-protein phosphorylation, in an attempt to gain insight into their molecular mode of action. Both Neoplatin and CHIP induced increased nuclear-protein phosphorylation in the YSS tumour cells, and loss of condensed chromatin. However, CHIP also induced increased nuclear-protein phosphorylation and loss of condensed chromatin in the YSR tumour cells. These changes correlated well with cell death. In addition Neoplatin, but not CHIP, treatment caused increased nuclear-protein phosphorylation in kidney tissues. This correlated with kidney damage as measured by blood urea levels. These selection criteria suggested that CHIP would be a more selective antitumour agent than Neoplatin, and will provide a basis for its comparison with the other 7 compounds.

Animals↗