Tissue Platinum Research Articles

Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs.

Previous work has shown platinum drugs to differ in their effects on the peripheral nervous system. To test whether their differential toxicity was due to differences in their partitioning into the peripheral nervous system, we correlated the hydrophobicity, reactivity, tissue accumulation and neurotoxicity of a series of eight platinum analogues. Neurotoxicity was detected by measuring sensory nerve conduction velocity (SNCV) in Wistar rats treated twice per week at the maximum tolerated dose. Tissue platinum concentrations were measured by inductively coupled plasma mass spectrometry. Hydrophobicity (log P) was measured using an octanol-aqueous shake-flask method. The half-life of platinum drug binding to plasma proteins in vitro was determined. The cumulative dose causing altered SNCV ranged from 15 to > 2050 μmol kg−1. Ranking of the compounds by their neurotoxic potency in rats (oxaliplatin >R,R -(DACH)PtC4> ormaplatin >S,S -(DACH)PtCl4>S,S -(DACH)Pt oxalato > cisplatin > carboplatin > JM216) correlated with the frequency of neurotoxicity in patients (r> 0.99;P< 0.05). Ranking the compounds by their peripheral nerve accumulation was cisplatin > carboplatin > oxaliplatin >R,R -(DACH)PtCl4≈S,S -(DACH)PtCl4and did not correlate with neurotoxicity. Log P ranged from – 2.53 to –0.16 but did not correlate with neurotoxicity. Log P correlated inversely with platinum accumulation in dorsal root ganglia (r2= 0.99;P = 0.04), sural nerve (r2= 0.85;P = 0.025), sciatic nerve (r2= 0.98;P = 0.0012), spinal cord (r2= 0.97, P = 0.018) and brain (r2= 0.98, P = 0.001). Reactivity correlated with neurotoxicity potency in rats (r2= 0.89, P = 0.0005) and with the frequency of neurotoxicity in patients (r2= 0.99, P = 0.0002). The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity. Differences in the reactivity of platinum complexes accounts for some of the variation in their neurotoxicity. © 2000 Cancer Research Campaign

Normalization of hyperglycaemia by oral vanadyl sulfate does not reverse diabetes-induced protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats.

Streptozotocin- and galactose-induced diabetic rats are protected against nephrotoxic effects of cisplatin. While the mechanism remains to be defined, protection is associated with a decrease in the accumulation of platinum in renal cortical tissues of streptozotocin-diabetic versus non-diabetic rats. A physiological abnormality common to streptozotocin and galactosemic models of diabetes is hyperglycaemia, suggesting that elevated sugars are involved in mediating protection of diabetic kidney against cisplatin nephrotoxicity. The current study focused on the effect of normalization of hyperglycaemia by vanadyl sulfate trihydrate on the initiation of protection and accumulation of platinum in kidneys of streptozotocin-diabetic rats. Streptozotocin-diabetic rats were treated with 0.75 mg/ml of vanadyl sulfate trihydrate in drinking water to normalize streptozotocin-induced hyperglycaemia. Vanadyl sulfate treatment normalized plasma glucose and glycosylated haemoglobin levels in streptozotocin-diabetic rats to values observed for non-diabetic rats. Intraperitoneal administration of cisplatin (5 mg/kg body weight) increased blood urea nitrogen by a factor >2.5 over baseline in both untreated and vanadyl-treated non-diabetic groups. Cisplatin-induced increases in blood urea nitrogen were 1.6 times baseline in both untreated and vanadyl-treated streptozotocin-diabetic rats. Renal platinum accumulation was significantly lower in streptozotocin-diabetic versus non-diabetic rats regardless of vanadyl sulfate treatment. Renal vanadium levels in all groups of diabetic rats were not significantly different from each other. These results indicate that normalization of plasma glucose levels with vanadyl sulfate in streptozotocin-diabetic rats did not reverse protection of streptozotocin-diabetic kidney against cisplatin nephrotoxicity.

Effects of lipo prostaglandin E 1 on distribution of cis-diamminedichloroplatinum in lung metastasis derived from Dunn osteosarcoma cell-inoculated mouse foot-pad

This study was designed to determine the effect of lipid microspheres containing prostaglandin E 1 (lipo PGE 1) on cis-diamminedichloroplatinum (CDDP) accumulation in primary and lung metastatic lesions. Sixty mice were divided into four groups, depending on whether or not an intra-foot-pad injection of Dunn osteosarcoma cells had been administered and on whether or not an intraperitoneal injection of lipo PGE 1 had been administered. CDDP was injected intraperitoneally into all the mice 6 weeks after the inoculation. Tumor colonies of spontaneous metastases in the left lung were found in 21 out of 30 tumor-inoculated mice at autopsy. Tissue platinum concentrations in the lungs with metastatic colonies and in the foot-pad tumors were significantly higher in the lipo PGE 1-administered mice than in those without treatment. Terminal deoxytransferase-mediated dUTP nick end labeling (TUNEL) assay showed marked localization of dying cells in the lung metastatic lesions of the lipo PGE 1-administered mice. The results of this study showed that pretreatment with lipo PGE 1 may augment the anti-tumor effects of CDDP at the tumor site.

Gamma Camera Imaging of Platinum in Tumours and Tissues of Patients after Administration of 191Pt-Cisplatin

The aim of this study was to visualize non-invasively the uptake of platinum in tumours and tissues after treatment with cisplatin. 191Pt-cisplatin was synthesized from 191PtCl4

口腔癌に対する浅側頭動脈より超選択的動注法を用いた化学療法の検討 組織内濃度と病理的効果

口腔癌に対する浅側頭動脈より超選択的動注法を用いた化学療法の検討 組織内濃度と病理的効果

Changes of tissue platinum concentration in human ovarian cancer-bearing nude mice who received an immunoconjugate consisting of an anti-cytokeratin-8 Mab and carboplatin.

Changes of tissue platinum concentration in human ovarian cancer-bearing nude mice who received an immunoconjugate consisting of an anti-cytokeratin-8 Mab and carboplatin.

New superselective intra-arterial infusion via superficial temporal artery for cancer of the tongue and tumour tissue platinum concentration after carboplatin (CBDCA) infusion.

We developed a new technique of superselective intra-arterial chemotherapy for tongue cancer using a modified (1.35 mm) angiographic catheter. The catheter was confirmed to be inserted into the lingual artery by the new technique. We measured the platinum concentrations in resected tumour tissues after infusion of carboplatin (CBDCA) at 20 mg/m2 over 30 min from 30 min before tumour resection in 12 patients with cancer of the tongue (6 patients: superselective intra-arterial infusion; 6 patients: conventional intra-arterial infusion). The mean platinum concentration in tumour tissue was 10.5 +/- 1.2 micrograms/g wet, which was more than twice higher than, and significantly different from, 4.3 +/- 3.8 micrograms/g wet by the conventional intra-arterial infusion method. This new superselective intra-arterial infusion method allows direct infusion of the anticancer agent into the artery supplying the tumour and is expected to become a new therapeutic modality for cancer of the tongue.

Determination of platinum in tumour tissues after cisplatin therapy by electrothermal atomic absorption spectrometry

A simple procedure is described for the determination of platinum in tumours after cisplatin therapy. Tumours were digested in 65% nitric acid by incubation at 37°C for 2 days and platinum analysed under optimum conditions by electrothermal atomic absorption spectrometry with Zeeman background correction. The reproducibility of measurements in general was better than ±2%. The calibration graph was linear from 30.0 up to 1000 μg l −1 of platinum, while the limit of detection (3 σ) was found to be 3.0 μg l −1 (sample volume 20 μl). Aqueous standard solutions and the standard addition method were applied in the calibration procedure. Under the recommended analytical conditions, the sample matrix did not influence the determination of platinum significantly. In 72% of samples analysed the differences between results obtained by the two calibration procedures did not exceed ±5%.

Tissue platinum after clinical treatment with cisplatin or carboplatin in tumor-bearing patients.

Tissue platinum (Pt) levels were measured in tumor-bearing patients treated with either cisplatin or carboplatin. Cisplatin was given by intra-arterial, intraperitoneal, and intravenous (iv) administrations. After death, vertebrae and intervertebral disks were removed from eight human subjects, and livers and kidneys were removed from the half of them. When cisplatin was administered intraperitoneally, Pt of the liver was higher than that of the kidney, and a high content of Pt was detected in the vertebra by comparing with the other administration methods. At the intra-arterial administration of cisplatin, Pt was mainly accumulated in the kidney. At the iv administration of cisplatin, a high level of Pt was found in the vertebra and intervertebral disk, especially at the highest value at 10.31 micrograms/g in the intervertebral disk of one case, whereas a low level of Pt was detected in the liver. On the contrary, it was found that the iv administration of carboplatin did not result in high accumulations of Pt in the liver, kidney, intervertebral disk, and vertebra. Therefore, Pt is accumulated in different organs, depending on the way cisplatin is administered, but Pt is accumulated least in them by the administration of carboplatin.

Distribution of platinum in human gynecologic tissues and pelvic lymph nodes after administration of cisplatin.

Defining tissue accumulation of platinum may be of importance, since it may provide a pharmacological explanation for organ-specific cisplatin activity. This study was conducted to evaluate the efficacy of cisplatin at the tissue level in different gynecologic organs. The doses administered were equivalent to those used in neoadjuvant chemotherapy regimens. Cisplatin was administered intravenously to patients with cervical or endometrial cancer 1 h before operation, and platinum accumulations in tissues were assayed by the atomic absorption method. Platinum accumulation was highest in the cervix and next highest in the myometrium in both cancers. Platinum accumulation in ovary and lymph node was only 0.58 and 0.57 times that in the myometrium, respectively. In patients with cervical cancer, the platinum accumulations in the myometrium and cervix were significantly higher than in the ovary and lymph node. Platinum accumulation in cervical cancer tissue was lower than in the myometrium and cervix, suggesting that delivery of cisplatin to a cervical cancer is somewhat more difficult than to the normal cervix. In patients with endometrial cancer, there was significantly more accumulation in the cervix than in the ovary and lymph node. These data indicated that cisplatin was easily distributed to the cervix and myometrium, but not to the ovary, lymph node, and cancer tissues.

Effect of L-histidinol on cisplatin nephrotoxicity in the rat.

The effect of L-histidinol (LHL) on the acute nephrotoxicity produced by cisplatin (CDDP; 6 mg/kg, i.v.) was investigated in the rat. Intraperitoneal administration of LHL (100 mg/kg x 5 doses, 2 h apart) starting 2 h prior to CDDP single injection produced significant protection of renal function. The attenuation of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione-S-transferase (GST) activity, and increased urine/serum creatinine ratio as well as increased creatinine clearance. LHL significantly ameliorated the toxic renal biochemical changes induced by CDDP. Renal lipid peroxides, glutathione levels and GST activity showed a marked tendency towards the normal values. Accumulation of platinum in renal tissues was significantly decreased in the presence of LHL. It is concluded that LHL can act as a nephroprotectant, and it is suggested that it would have beneficial effects on the kidney in clinical settings.

Continuous local injection of carboplatin into the uterine cervix for cervical and endometrial cancer: preliminary study.

Platinum compounds are thought to be concentration- and time-dependent, but intravenous (i.v.) administration does not afford prolonged high platinum concentration in tumor tissue. In order to examine the influence of long-term local continuous (LC) injection of carboplatin, a pharmacokinetic study was performed. Twenty-six patients with uterine cancer were included. I.v. administration (11 patients): carboplatin (210 mg) was given i.v. and samples of target tissue were obtained at operation about 2 or 24 h after administration. LC administration (15 patients): the 21-gauge needle was implanted at the uterine cervix, and carboplatin was injected continuously (30 mg/day) for 3, 7 or 14 days using an external pump. The tissue platinum concentration was measured in the pelvic organs. The mean platinum levels at the cervix and vaginal wall in the LC (7 days) group were higher than those in the i.v. (2 h) group (p < 0.01). With LC injection, sustained platinum levels were maintained in the pelvic organs for a long time, with very few side effects. LC injection may be advantageous on the basis of pharmacokinetics.

Does determination of tissue platinum levels by mass spectroscopy have potential for monitoring exposure of pharmacy personnel to platinum-based antineoplastic drugs? A pilot study

The mutagenic and carcinogenic properties of cyto toxic drugs have led to concern over potential haz ards to pharmacy personnel who are required to prepare cytotoxic drugs. The platinum compounds cisplatin and carboplatin are frequently used antican cer agents and are unique by virtue of their suitability for quantification by highly sensitive physical meth ods such as inductively coupled plasma mass spec troscopy (ICPMS). We have performed a pilot study of ICPMS determination of platinum levels in biological samples from pharmacists preparing chemotherapy, including platinum-based antineoplastic drugs. In pa tients treated with platinum compounds, elemental platinum was readily detected in plasma and whole leukocytes and bound to leukocyte DNA for at least 4 weeks after treatment. However, in 28 pharmacists from our institution (18 involved in preparation of platinum-based compounds, 10 controls), tissue plat inum levels were below the limit of detection (0.05 nmol/L) by ICPMS. ICPMS measurement of platinum levels has the potential to be used to monitor health care workers for exposure to platinum-based cytotox ics. Exposure may result from accidental exposure to a platinum-based compound or may be due to poor technique by personnel preparing chemotherapy doses. We are intending to institute a prospective monitoring policy to gather further data.

Comparison of three different methods for measurement of tissue platinum level

We attempted to make a comparison of three methods for tissue platinum; atomic absorption spectrometry (AAS), inductively coupled plasma atomic emission spectrometry (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS). The determination limits were 0.05 ng/mL on ICP-MS, 50 ng/mL on ICP-AES, and 200 ng/mL on AAS, and the recovery rates were 97.7 +/- 6.9% on ICP-MS, 69.0 +/- 3.0% on ICP-AES, and 102.4 +/- 4.0% on AAS, respectively. Platinum was detected by ICP-AES and ICP-MS in human vertebrae, but the level was higher by ICP-AES than by ICP-MS. In the mouse kidney treated with cisplatin, platinum was detected by ICP-MS, but not by ICP-AES. As cadmium gives the absorption peak close to platinum, cadmium was measured together with platinum by ICP-AES in the vertebrae. From these, ICP-MS is the most sensitive for measurement at tissue platinum. The sensitivity of ICP-AES looks worse for measuring the tissue platinum, and it is necessary to take care of the contaminant of metals, especially cadmium. AAS is not suitable for measurement of tissue platinum as in the vertebrae and kidneys, because platinum was not detectable by AAS.

Determination of platinum by neutron activation analysis in nerve tissue from rats treated with cisplatin.

The analytical method used for the determination of traces of platinum and gold in different tissues of Wistar rats is based on neutron activation analysis with radiochemical separation of gold. This separation is performed by electrolytic deposition of gold on a niobium cathode, which ensures the highest radiochemical purity without any spectral interference from calcium or other major elements. Corrections for the nuclear interference from double neutron capture, caused by the gold content of the samples, were found to be insignificant at the levels reported. The following neural tissues were analyzed for their content of platinum: the dorsal root ganglions as well as the dorsal and ventral part of the spinal cord. The highest level of platinum was found in dorsal root ganglions.

Correlation of total and interstrand DNA adducts in tumor and kidney with antitumor efficacies and differential nephrotoxicities of cis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin

Mixed amine platinum complexes have been identified as a new class of antitumor agents with activity in some cisplatin-resistant tumor models. cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such analog that we have evaluated in uivo and found it to have antitumor activity that was comparable to that of cisplatin in a solid murine fibrosarcoma tumor model. In contrast to the nephrotoxicity observed with cisplatin, the analog was free from inducing this side-effect. Pharmacokinetics of the two compounds administered i.v. at equitoxic dose levels to tumor-bearing mice indicated similar decay kinetics of total platinum in plasma, kidney and the tumor. Furthermore, DNA-platinum adducts of the two agents were similar in the tumor. Total adduct levels in the kidney, on the other hand, were significantly greater (P < 0.05) by up to 4-fold for cisplatin compared with the mixed amine analog. Likewise, the levels of interstrand cross-links of the two platinum complexes were comparable in the tumor, but significantly greater (P < 0.05) in the kidney for cisplatin. The data indicate that the greater renal levels of total and interstrand DNA-platinum adducts formed by cisplatin correlate with renal damage associated with this agent, and suggest that adduct levels, and not total tissue platinum levels, provide a more useful correlation with pharmacodynamic observations.

Preclinical toxicology and tissue platinum distribution of novel?oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates

Preclinical toxicology and tissue platinum distribution of novel?oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates

Kinetics of tissue disposition of cis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin in mice bearing FSaIIC tumors.

The clinical potential of mixed amine platinum(IV) complexes has been identified, and interest in this new class of antitumor agents has been heightened by demonstration of their activity in cisplatin-resistant neoplasms. These tetravalent platinum agents are expected to undergo a reductive reaction to form the corresponding platinum(II) drug prior to eliciting biological activity. cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such product that we evaluated with cisplatin in vivo, and we found the two complexes given i.v. or i.p. to have comparable activities against a solid murine fibrosarcoma. Following i.v. administration of the two compounds at equitoxic dose levels (20 mg/kg) to tumor-bearing mice, platinum levels in the plasma were consistently higher for cisplatin. Tissue platinum levels, in contrast, were comparable between the agents or higher for the mixed amine analog at the earliest (3-h) time point. The temporal profiles determined for the concentrations over 48 h were tissue- and/or drug-specific and could be described by terminal-phase constants or half-lives of platinum in most tissues. In the plasma, kidney, lung, and jejunum, platinum levels arising from both compounds decayed with half-lives of 24-92 h. The terminal-phase constants of platinum determined in the heart for the two complexes were not significantly different from zero, indicative of levels remaining steady, whereas the constants were negative in the spleen, indicative of an increase in tissue drug concentration. In the tumor, liver, and testes, positive values for the decay-phase constants corresponding to half-lives of 47, 256, and 79 h, respectively, were seen with the mixed amine complex; this pattern contrasted with that found for cisplatin, for which the terminal-phase constant was either zero or negative. In vitro binding studies demonstrated the mixed amine complex to be more reactive. Thus, the presence of one ammine and one cyclohexylamine carrier ligand in the mixed amine complex, as opposed to the diammine ligands in cisplatin, leads to an increase in drug distribution and an alteration in the kinetics of tissue binding and removal of platinum.

Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates.

The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0-19 micrograms/g) and second highest in the kidney (2.8-12 micrograms/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all < or = 3.1 micrograms/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 micrograms platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r = 0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase, P < 0.05) and JM225 (2.4-fold increase, P < 0.05), and elevated plasma ALT activity (44 +/- 33 IU/l) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6 x 10(9)/l, 2 days, 74% reduction), platelet count (nadir, 613 x 10(9)/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5 x 10(7) nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68% +/- 16% of control, NS) than for i.v. cisplatin (nadir maltase activity).(ABSTRACT TRUNCATED AT 400 WORDS)

In situ lung perfusion with cisplatin an experimental study

This research work was planned to evaluate the soundness of in situ lung perfusion as a regional administration modality of chemotherapeutic agents. Sixteen pigs were randomly divided into four groups and received cisplatin (2.5 mg/kg) through the pulmonary artery using one of the following techniques: stop-flow (Group 1); stop-flow/out-flow occlusion (Group 2); lung perfusion (Group 3); or lung perfusion with 5 mg/kg of infused drug (Group 4). Serial blood (carotid, pulmonary artery and vein) and tissue samples (lung and mediastinal node), were taken before, at completion of, and 5, 10, 15, 30, 60, 120, 180 and 240 minutes after cisplatin infusion for blood gas and platinum content measurement. Blood circulation was restored to the treated organ (for 60 minutes). The animals were killed, and specimens from lung, thyroid, esophagus, heart, liver, spleen, adrenal glands, kidney, bone marrow, stomach, ileum, colon, psoas muscle, and skin were obtained. Platinum concentrations in plasma, plasma ultrafiltrate (free platinum) urine, and tissues were determined by flameless atomic absorption spectroscopy. Lung damage was evaluated by light and electron microscopic examination. Greater systemic plasma, lower pulmonary plasma, and tissue platinum levels were detected when cisplatin was given using the stop-flow technique with respect to the other administration modalities. No significant difference in regional and systemic platinum exposure was found between Groups 2 and 3. However, lung perfusion resulted in higher mediastinal node and lower bone marrow platinum values. Morphologic alterations and impairment of gas exchanges in the treated lung were not dependent on the applied infusion technique. This study provides the pharmacokinetic rationale for the application of lung perfusion to patients with pulmonary metastases.