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PubMed1985

Secondary screening of platinum compounds in human ovarian cancer xenografts in nude mice.

Five TNO platinum compounds were evaluated for antitumor activities in two human ovarian carcinoma tumor lines grown in nude mice. The most active drug, TNO-38, was investigated in five additional lines with a known range of sensitivity to cisplatin. None of the new compounds showed superior activity to cisplatin. The slightly lower activity of TNO-38 as compared to the parent compound was reproducible in all tumor lines. Besides the similarity in the antitumor activity, a remarkable correspondence in platinum distribution and retention at 24 hr of TNO-38 and cisplatin could be observed. Chromatographic analysis of the compounds in their injection fluids showed single peaks for TNO-26 and TNO-38. The degradation products of the latter drugs may have affected their activity and toxicity. These human ovarian cancer xenografts may offer a reliable screening model for selection of a cisplatin analog with a higher therapeutic index or without cross-resistance for treatment in ovarian cancer.

Adenocarcinoma↗
PubMed1992

Flow cytometric analyses of the characteristics of tumor cells treated with two platinum compounds: 1,1-cyclobutanedicarboxylato(2-aminomethylpyrrolidine)- platinum(II) and cisplatin.

In order to reduce the toxicities of cisplatin (DDP) and/or to improve antitumor efficacy, a large number of new platinum analogues have been synthesized. 1,1-Cyclobutanedicarboxylato(2-aminomethylpyrrolidine)platin um(II) (DWA2114R) is one of them. In this study, we characterized the action mechanism of DWA2114R flow-cytometrically in 3 human lung cancer cell lines by using bromodeoxyuridine (BrdUrd), rhodamine 123 (Rho) and Ki-67 antibody (Ab), and compared the results with those for DDP. We found that the actions of these 2 platinum analogues were characteristically different at the subcellular level. Our observations may be summarized as follows. a) Simultaneous exposure of cells to DDP and BrdUrd resulted in decreases in fluorescence intensity, i.e. in the amount of BrdUrd incorporated into single-stranded DNA. b) DDP appears to be approximately 20-fold more active than DWA2114R in producing cell cycle perturbation. c) In PC-6 small cell carcinoma cells, DDP induced decreases in S phase cells and accumulation of cells in the G2M phase, whereas in PC-10 squamous carcinoma and PC-3 adenocarcinoma cells DDP produced S phase cell accumulation. Weak but similar changes occurred with DWA2114R. d) The high Ki-67 antigen cell population was decreased by treatment with either DDP or DWA2114R, but DDP reduced the low Ki-67 antigen population more than DWA2114R. e) In PC-10 and PC-6 cells, DDP suppressed Rho incorporation into live mitochondria, whereas DWA2114R produced no change in Rho incorporation. PC-3 cells were not affected by either DDP or DWA2114R. It is likely that these differences reflect the biological activities of DDP and DWA2114R.

Antineoplastic Agents↗
PubMedDate not supplied

Influence of a novel platinum compound--cis-dichloro (dimethylsulphoxide) (1-beta-D-rybofuranosyl-1,2,4-triazolo-3-arboxyamide) platinum (II)--"Pt-rib-1"--on cell cycle and apoptosis in ClS91 and B16 mouse melanoma in vitro.

Cisplatin has a significant role in the treatment of selected human tumors including advanced melanoma, but new platinum compounds are still in focus of search for better properties. Modern drug design is often based on studies detecting the abilities of tested drug to induce apoptosis and disturb cell cycle. Aim of the study was to establish the influence of a platinum complex Pt-rib-1 on cell cycle and apoptosis occurrence in mouse melanoma B16 and ClS91 cells. Pt-rib-1 is a ribavirin derivative. previously characterized and described as cytotoxic to B16 and ClS91 mouse melanoma cells in vitro. The new platinum complex (Pt-rib-1); cis- dichloro (dimethylsulphoxide) (1- beta- D-ribofuranosyl- 1,2,4-triazolo -3- carboxyamide) platinum (II) was supplied. Cisdiaminodichloroplatinum (II), (cisplatin) was used in control groups. To detect apoptotic and necrotic cells, Annexin V- conjugated with fluorescein isothiocyanate (Annexin V-FITC, Immunotech) and propidium iodide (IP, Immunotech) were used. Apoptosis detection were done using fluorescence microscopy and flow cytometry. The total DNA content within the cell indicated phase of the cell cycle. DNA content was measured using flow cytometry. Values given represent the mean from three determinations. Results were presented as mean +/- standard deviation (SD). Statistical analysis was done using t-Student test. There were 70.4% of apoptotic cells in the ClS91 culture after 24 h incubation with Pt-rib-1 at a concentration of 2.04 x 10(-3) M (4 x IC50). In B16 group, 83.2 per cent of apoptotic cells was found after 24h incubation with Pt-rib-1 at high concentration (2.30 x 10(-3) M). A 24-h experiment shows a threshold at a concentration higher than 3 x IC50 responsible for apoptosis induction in B16 and ClS91 cells. After 48 h incubation with Pt-rib-1 the per cent of apoptotic cells increased gradually with rising concentrations of Pt-rib-1 up to a final concentration of 2.04 x 10(-3) M and 0.92 x 10(-3) M in ClS91 and B16 groups, respectively. Cell accumulation was observed in S phase after 48 h incubation with Pt-rib-1. The per cent of cells in S phase increased from 31 to 51.1% and 38.8 to 50.0% in ClS91 and B16 culture, respectively. There were no B16 and ClS91 cells in G2/M phase after incubation with higher concentrations of Pt-rib-1 (from 0.2 to 2.0 x 10(-5) M/dm3). Pt-rib-1 partially exhibits action of cisplatin. which has no specific influence on cell cycle and ribavirin. probably responsible for DNA synthesis delay.

Animals↗
PubMed2003

A novel platinum compound inhibits telomerase activity in vitro and reduces telomere length in a human hepatoma cell line.

Telomerase activity is detectable in most human tumors but not in most normal somatic cells or tissues. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective strategy for antitumor therapy. In the present study, we found that platinum compounds, including cisplatin [cis-diamminedichloro-platinum (II)], strongly inhibited the activity of partially purified rat telomerase. Among the agents tested, 2,3-dibromosuccinato [2-(methylaminomethyl)pyridine]platinum (II) (compound E) exhibited the strongest inhibition, with an median inhibitory concentration (IC(50)) of 0.8 micro M. The mode of inhibition was noncompetitive with either dNTPs or TS (first) primer, with K(i) values estimated to be 2.3 or 3.9 micro M for varied TS primer or dNTPs, respectively. Notably, cisplatin also inhibited the telomerase activity, with an IC(50) of 2.0 micro M. Again, the mode of inhibition was noncompetitive, with K(i) values estimated as 7.3 or 8.1 micro M. Preincubation of TS primer with compound E did not affect the telomerase inhibition, whereas preincubation with cisplatin caused remarkable enhancement. Treatment of a human hepatoma cell line HepG2 with a low concentration of compound E gradually reduced the telomere length, indicating that this compound was able to inhibit telomerase in living cells as well as in vitro.

Animals↗
PubMed2007

6-year experience of concurrent radiochemotherapy with vinorelbine plus a platinum compound in multimorbid or aged patients with inoperable non-small cell lung cancer.

BACKGROUND AND PURPOSE: Although poor-risk patients represent no minority in inoperable non-small cell lung cancer (NSCLC), there is little experience with concurrent radiochemotherapy (RCT) in this group. Here, the authors report on the feasibility and efficacy of RCT with vinorelbine plus carboplatin or cisplatin in NSCLC patients with comorbidities and poor general health or advanced age. PATIENTS AND METHODS: A total of 66 patients (ten women, 56 men, median age 68 years) with inoperable NSCLC and an increased risk of treatment side effects (WHO performance score of 2-3; cardiac, pulmonary or renal failure or extensive weight loss before treatment, or an age of 71-78 years) were treated with vinorelbine 12.5 mg/m(2) on days 1, 8, 15, 29, 36, and 43 in combination with either carboplatin 70 mg/m(2) (n = 59) or cisplatin 20 mg/m(2) (n = 7) on days 1-5 and 29-33 in addition to receiving conventional fractionated radiotherapy with doses of up to 63 Gy (90% isodose). RESULTS: 62 of 66 patients (94%) reached the 90% level of the prescribed radiation dose, and 41/66 patient (62%) received at least two cycles of the platinum compound and four cycles of vinorelbine. The following hematologic side effects (CTC classification [Common Toxicity Criteria]) were observed: grade 3 (12%) and grade 4 (15%) thrombocytopenia, grade 3 (38%) and grade 4 (4%) leukocytopenia, and anemia requiring transfusion (26%). Other side effects (CTC) included grade 3 (3%) and grade 4 (2%) esophagitis and grade 3 pneumonitis (3%). The response rates were as follows: complete remission 18%, partial remission 56%, stable disease 21%, and progressive disease 5%. The cumulative survival rates were 53%, 24%, and 8% at 12 months, 24 months, and 5 years, respectively. CONCLUSION: After including a larger group of patients than in 2003 and following the patients for several years, the authors determine that concurrent RCT consisting of vinorelbine plus a platinum compound and conventional fractionated radiotherapy can be carried out with manageable toxicity, even in this negatively selected population of patients. Their survival rates were comparable to those achieved in other studies with simultaneous RCT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

[Clinical pharmacology of anticancer agents. (Part 1) Introduction, alkylating agents and platinum compounds].

Pharmacokinetic concepts as to absorption, distribution, metabolism and excretion of anticancer agents, and how drugs reach to the site of action were reviewed. Then, roles of the liver and kidney to the excretion and metabolism, intracellular pharmacokinetics, and relationships between drug response and cell proliferation kinetics or cell cycle phase were explained. Drug development, mode of action and pharmacokinetics of alkylating agents and platinum compounds were reviewed. This includes: alkylating agents: nitrogen mustard, phenylalanine mustard, estracyte, cyclophosphamide, carboquone, busulfan, nitrosourea, etc., and platinum compounds: cisplatin, carboplatin, 254-S, DWA-2114 R, NK-121.

Alkylating Agents↗
PubMed2002

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response.

Mononuclear and multinuclear platinum complexes are known to induce distinct types of DNA lesions and exhibit different profiles of antitumor activity, in relation to p53 mutational status. In this study, we investigated the cellular effects of exposure to two platinum compounds (cisplatin and the multinuclear platinum complex BBR 3464), in the osteosarcoma cell line, U2-OS, carrying the wild-type p53 gene and capable of undergoing apoptosis or cell cycle arrest in response to diverse genotoxic stresses. In spite of the ability of both compounds to up-regulate p53 at cytotoxic concentrations, exposure to BBR 3464 resulted in cell cycle arrest but only cisplatin was capable of inducing significant levels of apoptosis and phosphorylation at the Ser15 residue of p53. The cisplatin-induced protein phosphorylation, not detectable in cells treated with BBR 3464, was associated with RPA phosphorylation, a specific up-regulation of Bax and down-regulation of p21(WAF1). Cells treated with BBR 3464 displayed a different cellular response with evidence of cytostasis associated with a high induction of p21(WAF1). The regulation of p21(WAF1) after cisplatin or BBR 3464 exposure required a p53 signal, as documented using stable transfectants expressing a dominant-negative form of p53 (175(his)). Taken together, these results indicate that cellular response to different genotoxic lesions (i.e. apoptosis or growth arrest) is associated with a specific recognition of DNA damage and a different p53-mediated signaling pathway. Multinuclear platinum complexes could be regarded as useful tools for investigating the p53-mediated process of cell cycle arrest in response to DNA damage.

Amino Acid Sequence↗
PubMed1983

The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function.

Three divalent platinum compounds, cis-dichlorodiammineplatinum (cis-DDP), trans-dichlorodiammineplatinum (trans-DDP), and ammonium tetrachloroplatinate, were examined for their effects on glucose metabolism in male F-344 rats. Rats were treated with a single iv dose of cis-DDP (0, 2.5, or 5 mg/kg), trans-DDP (0, 5, 7.5, or 15 mg/kg) or tetrachloroplatinate (0, 6, or 18 mg/kg). Glucose tolerance was evaluated 2, 4, 7, and 14 days following platinum treatment by serially measuring plasma glucose before and following an ip glucose load. Administration of 5 mg/kg cis-DDP impaired glucose tolerance on Days 2 and 4, but not on Days 7 and 14. Plasma immunoreactive glucagon (IRG) was elevated at all times following cis-DDP treatment and thus was not correlated with the transient impairment in glucose tolerance. Plasma immunoreactive insulin (IRI) response to a glucose load was deficient relative to the degree of hyperglycemia in cis-DDP-treated (5 mg/kg) animals on Days 2 and 4. However, neither histopathological damage of the pancreas nor pancreatic stores of IRI were affected by cis-DDP treatment. In contrast to cis-DDP, equimolar or greater than equimolar doses of trans-DDP or tetrachloroplatinate did not significantly affect glucose tolerance at any time examined. These results indicate that cis-DDP-mediated glucose intolerance is unique to the geometry of the complex and is related to properties other than the presence of a divalent platinum atom. Furthermore, glucose intolerance following cis-DDP treatment appears to be related to a relative deficiency in insulin secretion.

Animals↗
PubMed2002

Second-line with paclitaxel and carboplatin for recurrent disease following first paclitaxel and platinum compounds in ovarian carcinoma.

OBJECTIVE: The combination of paclitaxel and platinum compounds is considered the best first-line regimen for advanced ovarian carcinoma. The purpose of this study was to evaluate a paclitaxel and carboplatin combination in pretreated patients who recurred within 24 months after a complete clinical response with the same regimen used as first-line chemotherapy. METHODS: 18 patients were included in this study. Second-line chemotherapy consisted of paclitaxel, 175 mg/m2 as a 3-hour infusion, and carboplatin AUC 6 every 21 days. RESULTS: Among 15 evaluable patients, eight (53%) complete and five (34%) partial responses were observed, while two (13%) patients had stable disease (SD). The response rate was 67% among patients with measurable disease and 52% for evaluable disease. The median progression-free interval after second-line chemotherapy was 8.3 months. The median progression-free interval for patients with measurable disease was 8.6 months and for evaluable disease it was 7.9 months. Seven (46%) of 15 patients have developed recurrence after second-line chemotherapy with paclitaxel and carboplatin with a median time to recurrence of 9.8 months. CONCLUSION: Paclitaxel 175 mg/m2 and carboplatin AUC 6 as second-line chemotherapy in this sensitive population is effective in terms of response rate and progression-free interval.

Adult↗
PubMed2005

The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines.

Raf kinase plays a central role in oncogenic signaling and acts as a downstream effector of Ras in the extracellular signal-regulated (ERK) kinase pathway. BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-beta. The present study evaluates the effects of combining BAY and platinum derivatives on human colorectal cancer cells using different incubation protocols. Our data show that the combination of oxaliplatin or cisplatin with BAY results in marked antagonism irrespective of the used application schedule. Furthermore, BAY abrogates the cisplatin-induced G2 arrest as well as the G1 arrest induced by oxaliplatin. BAY alone arrests cancer cells in their current cell cycle phase and affects cell cycle regulative genes. Specifically, BAY reduced the protein expression of p21Cip1 as well as cyclin D1, and inhibits the expression of cdc2 (cdk1). Utilizing atom absorption spectrometry, BAY significantly reduced cellular uptake of platinum compounds and thereby the generation of DNA adducts. Taken together, co-incubation with BAY results in reduced cellular uptake of platinum compounds and consecutively reduced generation of DNA adducts, and eventually decreased cellular cytotoxicity in human colorectal cancer cells. Our results indicate that the Raf kinase inhibitor BAY 43-9006 might also directly or indirectly interact with platinum transporter proteins in vitro.

Antineoplastic Agents↗
PubMed1995

Induction of the c-myc but not the cH-ras promoter by platinum compounds.

The recombinant plasmids p324, p330 and p323 carrying the aminoglycoside phosphotransferase (aph) gene and 5' flanking c-myc sequences linked to the reporter gene chloramphenicol acetyl-transferase (cat) were introduced into the mouse erythroleukaemic cell line F412B2TK- and stable transfectants resistant to geneticin G418 were obtained. The effects of cis-platin and two novel platinum compounds, D19466 (lobaplatin) and D17872, on c-myc promoter regions were studied using a large range of drug concentrations and correlated with cytotoxicity data. It was found that cis-platin and D19466 show a similar pattern of cytotoxicity and activation of c-myc promoter-driven cat gene expression with maximum effect (increased expression of 7.4- and 8.1-fold, respectively) at a concentration of 5 x 10(-5) M, while the less cytotoxic D17872 only slightly activates cat expression at the same concentration. However, when the F412B2TK- cell line was transfected with a plasmid carrying 5' flanking sequences of the c-Hras1 gene with promoter/enhancer function, linked to the cat reporter, no similar inductive effect was observed with any of the platinum drugs used. These data suggest that platinum compounds and possibly other DNA-damaging agents may specifically influence the expression of certain genes.

Animals↗
PubMed2004

Novel separation method for highly sensitive speciation of cancerostatic platinum compounds by HPLC-ICP-MS.

A high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) method is presented for analysis of cisplatin, monoaquacisplatin, diaquacisplatin, carboplatin, and oxaliplatin in biological and environmental samples. Chromatographic separation was achieved on pentafluorophenylpropyl-functionalized silica gel. For cisplatin, carboplatin, and oxaliplatin limits of detection of 0.09, 0.10, and 0.15 microg L(-1), respectively, were calculated at m/z 194, using aqueous standard solutions. (3 microL injection volume). The method was utilized for model experiments studying the stability of carboplatin and oxaliplatin at different chloride concentrations simulating wastewater and surface water conditions. It was found that a high fraction of carboplatin is stable in ultrapure water and in solutions containing 1.5 mol L(-1) Cl-, whereas oxaliplatin degradation was increased by increasing the chloride concentration. In order to support the assessment of oxaliplatin eco-toxicology, the method was tested for speciation of patient urine. The urine sample contained more than 17 different reaction products, which demonstrates the extensive biotransformation of the compound. In a second step of the study the method was successfully evaluated for monitoring cancerostatic platinum compounds in hospital waste water.

Antineoplastic Agents↗
PubMed2005

Presence of cancerostatic platinum compounds in hospital wastewater and possible elimination by adsorption to activated sludge.

Platinum originating from the excreted cancerostatic platinum compounds (CPC) cisplatin, carboplatin and oxaliplatin was monitored over a period of 28 days in the wastewater of the oncologic ward of the Vienna University Hospital. Concentration levels ranging from 4.7 to 145 microg L(-1) were measured by inductively coupled plasma mass spectrometry (ICP-MS). An average ratio of weekly drug emission/drug consumption of 0.27+/-0.12 was assessed. Model studies were carried out for fundamental understanding of CPC interaction with the solid phases present at different stages of the water cycle. Wastewater and activated sludge were spiked with CPC at concentration levels as found in the sewer of the oncologic ward. The platinum concentration remaining in the tested solution was measured after 24 h of incubation. Depending on pH, the three substances exhibited considerably different adsorption rates in wastewater. At pH 7, cisplatin was adsorbed by 88%, whereas only 26% of carboplatin and 54% of oxaliplatin were removed from the aqueous phase. Adsorption by activated sludge was higher, less affected by pH variation and comparable for all investigated CPC (96% for cisplatin, 70% for carboplatin and 74% for oxaliplatin at pH 6.8). In a next step, the dependence of CPC adsorption was tested for wastewater and activated sludge of different sampling sites. Strong variations were found only for wastewater, whereas activated sludge showed more consistent elimination rates (average values: cisplatin 92%, carboplatin 72%, and oxaliplatin 78%). These findings indicate that the major part of the excreted CPC is adsorbed by the solid phase in the water cycle and is thus expected to be removed from the wastewater by sewage treatment plants.

Adsorption↗
PubMed1976

Immediate (type I) allergic responses to platinum compounds.

A series of platinum complexes has been used for allergy tests in a number of platinum refinery workers who are known to be sensitive to hexachloroplatinate ([PtCl6]2-) salts. The results show that the allergy-eliciting compounds are confined to a very small group of ionic complexes containing reactive halogen ligands. Neutral complexes and those containing more strongly bound ligands are totally inactive. These variations in activity are interpreted in terms of established kinetic and thermodynamic parameters.

Chelating Agents↗
PubMed1990

The effect of some platinum compounds on the biosynthesis of RNA and its precursors.

The effect of cis-DDP (cis-diamminedichloroplatinum(II)), trans-DDP (trans-diamminedichloroplatinum(II)), SPC (spermine-platinum(II) complex), and K2PtCl4 on the ribomononucleotide and RNA metabolism was studied. When Ehrlich ascites tumor cells were preincubated with the aforementioned compounds and then labeled with [C14]uridine a clear-cut suppression of the radioactive labeling of RNA was observed. As radioactivity incorporated into the pool of the free uridine nucleotides in the cells treated with platinum compounds was even higher in comparison with that of the non-treated cells a conclusion may be drawn with certainty that the platinum compounds studied inhibit RNA biosynthesis. It was also found that under the effect of these compounds in the in vivo-assessed rate of the conversion of uridine nucleotides into cytidine nucleotides was considerably diminished. Using NaH14CO3 as a radioactive precursor it was shown that platinum compounds also inhibited purine biosynthesis de novo, in particular the conversion of IMP into GMP and AMP. The pronounced inhibitory effect of the platinum compounds on essential steps of the pyrimidine and purine biosynthesis de novo may be at least partly responsible for the firmly established inhibition in the present study of RNA biosynthesis by platinum compounds. The inhibition of the synthesis of the mononucleotides and RNA by the platinum compounds may be closely related to their cytostatic and cytotoxic activities.

Animals↗
PubMed1984

Chromosomal aberrations, sister chromatid exchange (SCEs) and micronuclei induction with three platinum compounds (cis-DDP, CHIP, CBDCA) in V79 cells in vitro.

Three platinum compounds (cis-DDP, CHIP, CBDCA) were tested or induction of chromosome aberrations and micronuclei as well as for SCEs in V79 cells in vitro. There was a clear relationship between the degree of inhibitory activity of the tested drugs and the increase of studied markers of cytogenetic damage. Statistical significance was proved in increase of SCEs values in cis-DDP and CHIP-treated cells when compared with untreated controls.

Animals↗
PubMed1992

Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds.

The role of glutathione (GSH) in the effectiveness of and resistance to 7 platinum compounds [5 Pt(II) and 2 Pt(IV) drugs] was evaluated in a 8.6-fold cisplatin (CDDP)-resistant human small cell lung cancer cell line (GLC4/CDDP), the parent GLC4 line, a 3.7-fold CDDP-resistant human embryonal carcinoma cell line (Tera-CP), and the parent Tera line (NTera2/D1). Resistance factors for both CDDP-resistant cell lines were determined after continuous incubation (4 days) with CDDP. Continuous incubation with the other studied platinum drugs revealed complete cross-resistance for carboplatin (CBDCA) and zeniplatin but less for enloplatin (ENLO) and iproplatin in both models. Tetraplatin and lobaplatin showed, respectively, partial and complete cross-resistance in GLC4/CDDP but no cross-resistance in Tera-CP. GSH level, but not glutathione S-transferase activity, of the 4 cell lines correlated with platinum drug concentrations inhibiting cell survival by 50% after continuous incubation (r = 0.86, P < 0.05). GSH depletion by DL-buthionine-S,R-sulfoximine (BSO) increased sensitivity, as measured after a 4-h exposure to the drugs, of GLC4/CDDP for CDDP 2.0-fold, for CBDCA 1.7-fold, for zeniplatin 1.7-fold, and almost to the level of the sensitive GLC4 for ENLO, whereas no effect was observed for lobaplatin and the Pt(IV) compounds iproplatin and tetraplatin. BSO-modulating effect was higher in the sensitive GLC4 line for most compounds; therefore reduction of resistance could be achieved only for CDDP and ENLO. In contrast to GLC4, no modulation occurred in Tera. In Tera-CP BSO increased sensitivity for CDDP 1.5-fold, for CBDCA 1.9-fold, and for zeniplatin 1.2-fold; no effect was observed for ENLO, lobaplatin, and the Pt(IV) compounds. Reduction of CDDP resistance by BSO was known to occur with identical cellular platinum levels and higher Pt-DNA binding in GLC4/CDDP. However, pretreatment with BSO followed by 4 h ENLO incubation increased cellular platinum levels in both GLC4 and GLC4/CDDP while Pt-DNA binding remained unchanged. In conclusion, GSH reflected sensitivity to platinum-containing drugs. However, since the involvement of GSH differed between the models and the various platinum drugs, the effect of modulation with BSO was unpredictable.

Antineoplastic Agents↗