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PubMed1990

Restorative effects of calmodulin antagonists on reduced cisplatin uptake by cisplatin-resistant human ovarian cancer cells.

In the present study, we attempted to determine effects of calmodulin antagonists (W-7 and W-5) on cisplatin uptake by human ovarian cancer cells, using KF cells derived from serous cystadenocarcinoma of the ovary and cisplatin-resistant cells (KFr). The degree of cisplatin resistance of the KFr cells was about 3.7-fold higher than that of the parent KF cells, with regard to the concentration of cisplatin required for 50% inhibition of cell proliferation (IC50). When KF and KFr cells were incubated with 10 micrograms/ml cisplatin for 4 hr, cisplatin-content in the KF cells was significantly higher than that in the KFr cells. When KF cells were incubated in the presence of W-7 (but not W-5), cisplatin uptake significantly increased, compared to cells treated with cisplatin alone. On the other hand, when KFr cells were incubated in the presence of 5 micrograms/ml W-7 or W-5, cisplatin uptake was significantly higher than uptake by KFr cells treated with cisplatin alone, being comparable to that by KF cells treated with cisplatin alone. Such an increase in cisplatin uptake seemed to bring about adjuvant effects to cisplatin of KFr cell proliferation in vitro. The KF tumor grown in nude mice took up 24.8 ng/g dry wt of cisplatin 4 hr after intraperitoneal administration. When cisplatin was administered with calmodulin antagonists, cisplatin uptake by the KF and KFr tumors was significantly increased, compared to that after treatment with cisplatin alone. In particular, the cisplatin uptake by the KFr tumor was about 2.5-fold higher than that by the KFr tumor treated with cisplatin alone. These results suggest that coadministration of calmodulin antagonists and cisplatin may be of use in patients with refractory ovarian cancer.

Biological Transport↗
PubMed2000

Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal--regulated protein kinases 1 and 2 in a series of cisplatin-resistant ovarian carcinoma cell lines.

The cellular response to cisplatin involves activation of multiple signal transduction pathways, including the mitogen-activated protein (MAP) kinase pathways. In this study, we compared the cisplatin-induced activation of two MAP kinases, c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), in the cisplatin-sensitive ovarian carcinoma cell line A2780 and its derivative cisplatin-resistant cell lines CP70 and C200. Dose-dependent and time-dependent activation of JNK1 and ERK1/2 occurred in each of the three cell lines in response to cisplatin treatment. The requirement of higher concentrations of cisplatin for induction of maximum activation of JNK1 and ERK1/2 was correlated with increased levels of cisplatin resistance. In addition, inhibition of cisplatin-induced ERK activation, using the MAP/ERK kinase 1 synthetic inhibitor PD98059, resulted in enhanced sensitivity to cisplatin in all three cell lines. These results suggest that cisplatin-induced ERK1/2 activity is not responsible for the acquired cisplatin resistance in CP70 and C200 cells but rather provides a general cytoprotective effect in both cisplatin-sensitive and cisplatin-resistant cell lines. In conclusion, different patterns of cisplatin-induced JNK1 and ERK1/2 activation are observed in cell lines with different levels of cisplatin sensitivity, and inhibition of cisplatin-induced ERK1/2 activation enhances sensitivity to cisplatin in both cisplatin-sensitive and cisplatin-resistant cell lines.

Antineoplastic Agents↗
PubMed1997

Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods.

OBJECTIVE: To assess factors that affect cisplatin nephrotoxicity. METHODS: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. RESULTS: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2-5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. CONCLUSIONS: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes: (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

Antineoplastic Agents↗
PubMed2004

Combined gamma-irradiation and subsequent cisplatin treatment in human squamous carcinoma cell lines sensitive and resistant to cisplatin.

PURPOSE: To investigate the effects of combined radiation and subsequent cisplatin treatment on the human squamous carcinoma cell line SCC-25 and its cisplatin-resistant derivative SCC-25/CP. MATERIALS AND METHODS: SCC-25 and SCC-25/CP cells were treated with various gamma-ray doses (5 cGy-7 Gy) followed 60 min later by cisplatin treatment and subsequently assayed for survival using a conventional colony assay. For SCC-25, the subsequent cisplatin treatment was 0.1, 1, 10 and 20 microM for 1 h. For the more cisplatin-resistant SCC-25/CP cells, the subsequent cisplatin treatment was 10 and 50 microM for 1 h. RESULTS: The cisplatin-resistant SCC-25/CP cells were not cross-resistant to gamma-irradiation. Subsequent treatment with an LD50 concentration of cisplatin (10 and 50 microM for SCC-25 and SCC-25/CP, respectively) resulted in radiosensitization for SCC-25/CP but not for SCC-25 cells. Gamma-irradiation of SCC-25/CP cells followed by treatment with 10 and 50 microM cisplatin for 1 h resulted in radiation survival curves displaying a significant low-dose hypersensitive region followed by increased radioresistance at higher doses. A total of 10 microM cisplatin resulted in radiosensitization confined to the low-dose region (0.05 and 0.25 Gy), whereas the higher cisplatin treatment of 50 microM resulted in the appearance of a hypersensitive region together with a reduction of the increased radioresistance region. In contrast, cisplatin treatment (0.1, 1, 10 and 20 microM for 1 h) of SCC-25 cells had no significant effect on survival following 2.5 or 7.0 Gy and actually resulted in an increased low-dose radiation survival (0.05, 0.25 and 1 Gy) when survival was corrected for cisplatin treatment (p<0.01 for all cisplatin concentrations tested). CONCLUSIONS: The significant radiosensitization for SCC-25/CP given subsequent treatment with 50 microM cisplatin indicates cisplatin can inhibit the increased radioresistance response in SCC-25/CP cells. In contrast, the subsequent cisplatin treatment of SCC-25 cells can enhance their survival following low radiation doses.

Antineoplastic Agents↗
PubMed1993

Taxol effect on cisplatin sensitivity and cisplatin cellular accumulation in human ovarian cancer cells.

Taxol and cisplatin are the two most effective agents discovered to date for treating advanced-stage cancer of the ovary. Learning how best to combine these agents is the focus of preclinical and clinical studies conducted at a number of institutions. Taxol's effect on cellular sensitivity to cisplatin was studied in paired cisplatin-sensitive A2780 and cisplatin-resistant A2780/CP70 human ovarian cancer cell lines. Cisplatin growth curves were generated under conditions of specific sequencing with Taxol, and IC50s (concentrations at which growth is inhibited to 50% of control) for cisplatin were obtained and compared. Taxol was used at an IC10 dose in all experiments. Taxol treatments were for 24 hours and cisplatin treatments were for 1 hour in all experiments. Dimethyl sulfoxide (DMSO) was the diluent for all Taxol stock solutions. Separately, the effects of Taxol and DMSO on cisplatin cellular accumulation were measured. End points reported include measures of cytotoxicity and Taxol effects on cisplatin cellular accumulation. Using a microculture tetrazolium assay, cisplatin growth curves were obtained under the influence of Taxol, at a Taxol dose of 3 nM for both cell lines. DMSO alone had no effect on tumor cell growth. In A2780 cells, the influence of Taxol on cisplatin cytotoxicity was modest, whereas cisplatin-induced cell kill was augmented 1.5-fold when cisplatin was given immediately after Taxol. In A2780/CP70 cells, Taxol augmented cisplatin-induced cell kill by 30-fold when cisplatin was given immediately after Taxol; 75-fold when cisplatin was given 24 hours after completion of Taxol; and 19-fold when cisplatin was given 48 hours after completion of Taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin↗
PubMed1999

Enhancement of cisplatin cytotoxicity by terbium in cisplatin-resistant MDA/CH human breast cancer cells.

PURPOSE: The development of cisplatin resistance is a major problem in the treatment of cancer patients with cisplatin chemotherapy. The membrane binding of terbium (Tb3+) has been shown to increase the cellular accumulation of cisplatin in breast cancer cells. Therefore, the ability of Tb3- to modulate the cytotoxicity of cisplatin was investigated in cisplatin-sensitive (MDA) and cisplatin-resistant (MDA/CH) MDA-MB-231 human breast cancer cells. METHODS: The cytotoxic parameters of cisplatin were determined using live cell microfluorometry and median effect analysis. RESULTS: MDA/CH cells (IC50 = 142 +/- 9 microM) were found to be approximately 3.3-fold more resistant to cisplatin than MDA cells (IC50 = 43.5 +/- 3.0 microM). In both cell lines, the IC50 value for cisplatin was reduced two-fold in the presence of 80 microM Tb3+, thus indicating that the cytotoxicity of cisplatin is increased by Tb3+. The cytotoxic activity of cisplatin alone was observed to be 5.7 and 1.6 times more potent than that of Tb3+ alone in MDA and MDA/CH cells, respectively. Combination index analyses revealed that the interaction between cisplatin and Tb3+ was only synergistic at very low indices of cell death in MDA cells. However, in MDA/CH cells, the two drugs were synergistic up to intermediate levels of cell death. CONCLUSIONS: Our results suggest that the enhancement of cisplatin cytotoxicity by Tb3- is more effective in cisplatin-resistant MDA/CH cells than in cisplatin-sensitive MDA cells. Therefore, terbium is potentially useful in cisplatin combination therapy for breast cancer patients, especially for those patients who have developed resistance to the drug.

Breast Neoplasms↗
PubMed2003

Cisplatin tumor concentrations after intra-arterial cisplatin infusion or embolization in patients with oral cancer.

BACKGROUND: One neoadjuvant course of intra-arterial high-dose cisplatin (cis-diamminedichloroplatinum [CDDP]) tumor perfusion combined with intravenous sodium thiosulfate (STS) (cisplatin neutralizer) infusion is part of a multimodality concept for treatment of oral cancer. Recently, crystalline cisplatin embolization has been described as a novel treatment variant with increased tumor response rates. METHODS: We have compared tumor and plasma concentrations of cisplatin and STS by means of microdialysis in 10 patients with oral cancer treated with intra-arterial cisplatin perfusion (150 mg/m(2) in 500 mL of 0.9% sodium chloride) and 6 patients with oral cancer treated with crystalline cisplatin embolization (150 mg/m(2) in 45-60 mL of 0.9% sodium chloride), respectively. The microdialysis catheter was placed into the tumor, and the intra-arterial catheter into the tumor-feeding artery. Cisplatin was rapidly administered through the intra-arterial catheter and STS (9 g/m(2)) was infused intravenously to reduce the systemic toxicity of cisplatin. STS infusion was started 10 seconds after the cisplatin infusion was started. RESULTS: After embolization, cisplatin tumor maximum concentration (C(max)) and tumor area under the concentration-time curves (AUCs) were about 5 times higher than those achieved after intra-arterial perfusion (C(max), 180.3 +/- 62.3 micromol/L versus 37.6 +/- 8.9 micromol/L), whereas the opposite was true for plasma concentrations (C(max), 0.9 +/- 0.2 micromol/L versus 4.7 +/- 0.6 micromol/L). STS plasma levels were about 3 times higher than its tumor concentrations (C(max) tumor, 1685 +/- 151 micromol/L; C(max) plasma, 5051 +/- 381 micromol/L). After the standard intra-arterial perfusion, the average STS/CDDP AUC ratios for tumor and plasma were 211 +/- 75 and 984 +/- 139, respectively. After cisplatin embolization, the respective ratios were 48.5 +/- 29.5 and 42966 +/- 26728. CONCLUSION: Molar STS/CDDP ratios of greater than 500 are required outside the tumor to neutralize cisplatin, whereas tumor ratios should be lower than 100 to avoid a loss of tumor cell killing. The first goal is achieved with both treatment modalities and the second only with cisplatin embolization, suggesting that crystalline cisplatin embolization is superior to intra-arterial cisplatin perfusion in terms of tumor cisplatin concentrations. Whether this translates into higher tumor response rates needs to be investigated further.

Adult↗
PubMed2002

Simultaneous determination of intact cisplatin and its metabolite monohydrated cisplatin in human plasma.

Cisplatin is a cytotoxic platinum compound, used in the treatment of several solid tumors. Cisplatin and to a greater extent its hydrolysis product monohydrated cisplatin are responsible for side-effects like nephrotoxicity. A sensitive, accurate and precise method was developed to simultaneously determine cisplatin and monohydrated cisplatin in plasma. The compounds were separated by high-performance liquid chromatography and quantified by off-line furnace atomic absorption spectrophotometry. The linear ranges for cisplatin and monohydrated cisplatin in deproteinized plasma were 60-600 and 87.5-700 nM, respectively. From plasma, the mean recovery of cisplatin was 83.2% and that of monohydrated cisplatin 79.1%. The lower limits of quantification of cisplatin and monohydrated cisplatin in deproteinized plasma were 60 and 87.5 nM, respectively. Over the whole calibration range, the within- and between-day accuracy of intact cisplatin ranged from 100.7 to 111.4 and 94.8-102.0%, respectively. The within- and between-day accuracy of monohydrated cisplatin ranged from 107.1 to 113.3 and 101.4-104.9%, respectively. The within-day and between-day precision of cisplatin ranged from 3.4 to 11.5 and 7.3-10.3%, respectively. For monohydrated cisplatin, the within-day and between-day precision ranged from 3.7 to 6.2 and 5.6-7.9%, respectively. Currently, the developed assay has been implemented in pharmacokinetic studies of patients treated with cisplatin alone or in combination with other drugs.

Antineoplastic Agents↗
PubMed1996

Metoclopramide as a modulator of cisplatin: effects on pharmacokinetcs and cisplatin-DNA adducts in tumor and normal tissue.

The antiemetic drug metoclopramide (MCA) has previously been shown to cause DNA damage, to inhibit DNA repair and to enhance the effect of the chemotherapeutic agent cisplatin. Cisplatin acts by binding to DNA and thus forming cisplatin-DNA adducts. The present study was designed to investigate whether MCA affects the pharmacokinetics of cisplatin and the levels of cisplatin-DNA adducts in tumor and kidney. The effect on kidney is of special interest since cisplatin is highly nephrotoxic. Nude mice with xenografted squamous cell carcinoma where injected with cisplatin 5 mg/kg i.p. alone or in combination with MCA 2 mg/kp i.p. MCA was given 8 h after cisplatin. Total platinum was measured in serum and cisplatin-DNA adducts were analyzed in tumor and kidney with quantitative immunohistochemistry at 1, 9 and 24 h after cisplatin administration. The efficacy after treatment with cisplatin, MCA or cisplatin + MCA was studied in terms of tumor size measurements during 3 weeks following treatment and our previous observation that MCA enhances the cisplatin cytotoxicity was confirmed. The addition of MCA to cisplatin resulted in a slight increase in serum-platinum concentrations at 9 h and increased levels of adducts in tumors at 24 h. There was a tendency, however, not statistically significant, for increased adducts also in kidney. Thus, our findings may indicate that the sensitization of MCA on the cytotoxicity of cisplatin is mediated by increased formation, maybe accompanied by inhibited repair, of cisplatin-DNA adducts.

Animals↗
PubMed2003

Gemcitabine potentiates cisplatin cytotoxicity and inhibits repair of cisplatin-DNA damage in ovarian cancer cell lines.

Synergistic cytotoxicity between cisplatin and the nucleoside analog gemcitabine was observed in a panel of cisplatin-sensitive (2008, A2780) and -resistant (2008/C13*5.25, A2780/CP70) human ovarian cell lines. Previous studies have suggested a role for DNA repair in the mechanism of synergy between the two drugs. We therefore further investigated the hypothesis that the synergistic cytotoxicity between gemcitabine and cisplatin in these cell lines may be caused by gemcitabine-mediated inhibition of cisplatin intrastrand adduct (IA) and interstand cross-link (ICL) repair. The effect of gemcitabine on the accumulation and repair of cisplatin IA and ICL in each cell line was then measured directly using gene-specific quantitative polymerase chain reaction and denaturation/renaturation techniques, respectively. Pretreatment of 2008 cells with 1 microM gemcitabine for 2 h before exposure to cisplatin for 7 h enhanced the accumulation of cisplatin IA and ICL by 50 and 40%, respectively (P < 0.05), above that induced by cisplatin alone. To investigate the possibility that the increased accumulation of cisplatin lesions was caused by inhibition of removal of cisplatin damage, 2008 cells were incubated with 200 microM cisplatin for 5 h in the presence and absence of gemcitabine and then a further 8 h in the absence of cisplatin. Only 57% IA were removed in the combination treated cells compared with 74% in cisplatin control cells. Similarly, repair of cisplatin ICL was inhibited in the gemcitabine-treated cells compared with the cells treated with cisplatin only (60 versus 72%). These findings demonstrate a direct inhibitory effect of gemcitabine on the repair of cisplatin IA and ICL and suggest a mechanistic basis for the cytotoxic synergy between the two drugs.

Antimetabolites, Antineoplastic↗
PubMed2002

Retreatment with dose-dense weekly cisplatin after previous cisplatin chemotherapy is not complicated by significant neuro-toxicity.

Cisplatin induces a cumulative dose-dependent axonal sensory neuropathy. With a cumulative dose over 600 mg/m2, a significant percentage of patients will develop a moderate or severe neuropathy. We retreated patients with progressive or recurrent ovarian cancer after previous platinum-containing chemotherapy with weekly 50-70 mg/m2 cisplatin for six cycles. This group was prospectively followed for the development of neuropathy. Patients received six weekly cycles of either 50 or 70 mg/m2 cisplatin, combined with oral etoposide. Responding patients continued treatment with daily oral etoposide for nine months. Neurological toxicity was assessed with a sensory sum score, the sensory neuropathy common toxicity criteria (CTC) and quantitated sensory analysis of the vibration perception threshold (VPT). Neurological assessment was scheduled at baseline, after three cycles, at the end of cisplatin chemotherapy and at 3 monthly intervals until 1 year after the discontinuation of chemotherapy. The first evaluation carried out in the interval of 1-4 months after the end of weekly cisplatin therapy was taken as the principle evaluation for neurotoxicity because during this time interval the nadir of cisplatin neurotoxicity is to be expected. Of 89 patients evaluated for neurological toxicity, 80 patients were fully evaluable. Forty-nine had received prior cisplatin (median cumulative dosage 450 mg/m2); the others had received prior treatment with carboplatin. Cisplatin pretreated patients had slightly higher neuropathy scores at the start of weekly cisplatin. Almost all cisplatin pretreated patients received six cycles of cisplatin, 29 at 50 mg/m2 and 20 at 70 mg/m2 per cycle. Despite treatment up to an overall cumulative dose of 750-900 mg/m2 cisplatin, only 1 patient discontinued treatment due to neurotoxicity. One other patient developed a grade 3 neuropathy during follow-up. Only a marginal increase of neuropathic signs and symptoms were observed in all the other patients. In multiple regression analysis, the increase in VPT or the sensory sum score was not related to prior treatment (cisplatin or carboplatin). Patients with mild signs of neuropathy after prior treatment with cisplatin to a cumulative dose level of 400-450 mg/m2 can be retreated with weekly cisplatin to a cumulative dose of 420 mg/m2 (overall cumulative dose up to 800-900 mg/m2) with only a minimal risk of significant neurotoxicity.

Adult↗
PubMed2000

Treatment with paclitaxel alone rather than combination with paclitaxel and cisplatin may be selective for cisplatin-resistant ovarian carcinoma.

BACKGROUND: We have previously reported that paclitaxel (taxol) results in cisplatin sensitization to human ovarian cancer cells with cisplatin resistance in vitro. This study was designed to determine effects of taxol and its combination with cisplatin on growth of cisplatin-sensitive cell line (KF28) and the cisplatin-resistant counterpart (KFr13) in nude mice. METHODS: From 14 days after tumor inoculation treatment was initiated. Taxol (3 mg/kg) and cisplatin (2 mg/kg) were administered i.p. once a week for 5 weeks. RESULTS: In nude mice bearing cisplatin-sensitive cells (KF28), taxol followed by cisplatin and cisplatin plus taxol inhibited significantly (P < 0.05) the tumor growth rate compared with that in nude mice treated with cisplatin alone or taxol alone and cisplatin followed by taxol. On the other hand, in nude mice bearing cisplatin-resistant KFr13 cells, treatment with taxol alone inhibited completely the tumor growth rate, whereas no schedule-dependent interaction of taxol with cisplatin was observed. CONCLUSION: These results suggest that treatment with taxol alone may be superior to combination of taxol with cisplatin in patients with cisplatin-resistant ovarian carcinoma.

Animals↗
PubMed1994

A three-arm trial of vinorelbine (Navelbine) plus cisplatin, vindesine plus cisplatin, and single-agent vinorelbine in the treatment of non-small cell lung cancer: an expanded analysis.

Phase II studies have demonstrated that vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) alone or in combination with cisplatin has promising activity against non-small cell lung cancer (NSCLC). On the basis of these preliminary trials, a phase III study was designed to compare intravenous vinorelbine (30 mg/m2 weekly) plus cisplatin (120 mg/m2 on day 1 and day 29 and then every 6 weeks) with vindesine (3 mg/m2 weekly for 6 weeks and then every 2 weeks) plus cisplatin, and to evaluate whether the best of these regimens afforded a survival benefit compared with intravenous vinorelbine alone, an outpatient regimen. This report presents an expanded analysis of data from this previously published study. Six hundred twelve patients were enrolled in this trial: 206 in the vinorelbine plus cisplatin arm, 200 in the vindesine plus cisplatin group, and 206 in the single-agent vinorelbine arm. The vinorelbine plus cisplatin regimen was superior to the other two arms of the study in objective response rate (30% v 19% for vindesine plus cisplatin [P = .02] and 14% for vinorelbine alone [P = .001]), median survival duration (40 weeks v 32 weeks for vindesine plus cisplatin and 31 weeks for vinorelbine alone), and 1-year survival rate (35% v 27% for vindesine plus cisplatin and 30% for vinorelbine alone). An adjusted log-rank test provided a significant advantage for vinorelbine plus cisplatin when compared with vindesine plus cisplatin (P = .04) and with vinorelbine alone (P = .02). The major difference in survival between the two cisplatin-containing regimens occurred in patients with metastatic (stage IV) NSCLC. The incidence of granulocytopenia was significantly higher in the vinorelbine plus cisplatin arm compared with the other two treatment groups, but neurotoxicity was significantly more frequent in the vindesine plus cisplatin group. The results of this study indicate that the combination of vinorelbine plus cisplatin is a viable treatment option for patients with NSCLC and may provide advantages compared with other commonly used regimens.

Aged↗
PubMed1993

Modulation of cisplatin sensitivity and accumulation by amphotericin B in cisplatin-resistant human lung cancer cell lines.

To ascertain whether resistance to cis-diamminedichloroplatinum(II) (cisplatin) could be overcome, we determined the effects of amphotericin B (AmB), an antifungal agent, on cisplatin cytotoxicity, cisplatin-induced DNA interstrand cross-links formation, and cellular accumulation of cisplatin in human lung cancer cell lines, PC-9, PC-14, PC-7, and H69 and their corresponding respective cisplatin-resistant sublines PC-9/CDDP, PC-14/CDDP, PC-7/CDDP, and H69/CDDP in vitro. In PC-9/CDDP but not PC-9 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 micrograms/ml) of AmB was combined with cisplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), and cis-diammine(glycolato)platinum(II). Sensitizing effects of AmB of varying magnitudes on cisplatin cytotoxicity also were observed in all the other cell lines except PC-14. AmB-induced increases in cisplatin-induced interstrand cross-links formation were observed, the magnitudes of which corresponded to the magnitudes of AmB-augmented cisplatin cytotoxicity. Increased intracellular cisplatin accumulation was observed in the presence of AmB in all the cells that were sensitized to cisplatin by AmB. Therefore, the increases in cisplatin accumulation were considered to be responsible, at least in part, for the mechanism of the sensitizing effect. Further experiments using other human lung cancer cell lines showed that cells that were more resistant to cisplatin were more sensitized to cisplatin by AmB than cells that were cisplatin-sensitive.

Amphotericin B↗
PubMed2000

Prevention of cisplatin-induced nephrotoxicity by methimazole.

Nephrotoxicity is a dose-limiting factor in the use of cisplatin against solid tumours. Methimazole, an antithyroid drug containing a free SH group, has a nephroprotective potential against chemically-induced nephrotoxicity. We tried to explore the nephrotoxic effect of the experimentally therapeutic dose of cisplatin (7 mg kg(-1), i.p.), particularly on the nuclear level of kidney cells in male albino rats, as well as the possible protective effect of methimazole. Furthermore, the drug interaction regarding the oncolytic effect of cisplatin was examined in Ehrlich ascites carcinoma (EAC)-bearing mice. A single dose of cisplatin caused kidney damage, 6 days after injection, manifested by 219% increase in serum creatinine, 384% increase in blood urea nitrogen and 170% increase in kidney content of lipid peroxides. Kidney DNA showed clear fragmentations detected by gel electrophoresis. However, kidney reduced glutathione was unchanged at that time period. Histological examination of kidney confirmed the toxic effect of cisplatin. Methimazole (40 mg kg(-1), i.p., 30 min before cisplatin injection) significantly protected the kidney from the nephrotoxic effect of cisplatin as judged from the biochemical parameters investigated as well as the histopathological examination. On the other hand, the survival data in EAC-bearing mice treated with both drugs indicated the persistence of an effective cytotoxic action. This study points to a promising use of this combination and necessitates further experimental and clinical studies.

Animals↗
PubMed1997

Cell cycle perturbations in cisplatin-sensitive and resistant human ovarian carcinoma cells following treatment with cisplatin and low dose rate irradiation.

PURPOSE: To investigate cell cycle pertubations in plateau-phase human ovarian carcinoma cells following treatment with cisplatin, low dose-rate irradiation (LDRI), or combined cisplatin and LDRI, in order to understand cell cycle mechanisms by which these two treatment modalities interact. METHODS: Human ovarian carcinoma cells sensitive (A2780) and resistant (2780CP) to cisplatin were grown to plateau phase and given protracted cisplatin treatments (A2780 0.7 and 2 microg/ml; 2780CP 5 and 15 microg/ml) and/or LDRI (0.41 cGy/min). Cell cycle distribution following treatment was determined by two-parameter flow cytometry, based on bromodeoxyuridine (BrdU) uptake and DNA content using propidium iodide staining. RESULTS: The cisplatin-sensitive A2780 cells exposed to cisplatin alone for up to 28 h showed depletion of the G1 fraction and accumulation in S-phase, although the percentage of S-phase cells actively incorporating BrdU dropped to almost zero. The cisplatin-resistant 2780CP cells exposed to cisplatin alone showed a G1 arrest when exposed to 15 microg/ml, but not when exposed to 5 microg/ml. LDRI alone caused little cell cycle redistribution different from controls in either cell line. When LDRI was combined with cisplatin, no significant cell cycle redistribution was observed, apart from a decline in the actively incorporating S-phase fraction. CONCLUSIONS: Cisplatin caused A2780 cells to accumulate in nonincorporating S-phase, with no evidence of G1 arrest. Cisplatin-resistant 2780CP cells showed a G1 block when exposed to a high enough cisplatin concentration. This could indicate a mechanism of cisplatin resistance in these cells. LDRI alone or in combination with cisplatin did not result in significant cell cycle redistribution.

Bromodeoxyuridine↗
PubMed2002

Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer.

BACKGROUND: Irinotecan hydrochloride, a topoisomerase I inhibitor, is effective against small-cell lung cancer. In a phase 2 study of irinotecan plus cisplatin in patients with extensive small-cell lung cancer, there was a high response rate and a promising median survival time. METHODS: We conducted a multicenter, randomized, phase 3 study in which we compared irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive (metastatic) small-cell lung cancer. RESULTS: The planned size of the study population was 230 patients, but enrollment was terminated early because an interim analysis found a statistically significant difference in survival between the patients assigned to receive irinotecan and cisplatin and those assigned to receive etoposide and cisplatin; as a result, only 154 patients were enrolled. The median survival was 12.8 months in the irinotecan-plus-cisplatin group and 9.4 months in the etoposide-plus-cisplatin group (P=0.002 by the unadjusted log-rank test). At two years, the proportion of patients surviving was 19.5 percent in the irinotecan-plus-cisplatin group and 5.2 percent in the etoposide-plus-cisplatin group. Severe or life-threatening myelosuppression was more frequent in the etoposide-plus-cisplatin group than in the irinotecan-plus-cisplatin group, and severe or life-threatening diarrhea was more frequent in the irinotecan-plus-cisplatin group than in the etoposide-plus-cisplatin group. CONCLUSIONS: Irinotecan plus cisplatin is an effective treatment for metastatic small-cell lung cancer.

Adult↗
PubMed1994

Active efflux system for cisplatin in cisplatin-resistant human KB cells.

Mutants, KCP-4 and PC-5, resistant to an anticancer agent, cisplatin, were selected in multiple steps from human epidermoid KB carcinoma cells and human prostate PC-3 carcinoma cells, respectively. KCP-4 and PC-5 were 63 and 10 fold more resistant to cisplatin than the parental cells, respectively. KCP-4 cells exhibited increased resistance to cisplatin analogues and were also slightly cross-resistant to melphalan, cyclophosphamide, mitomycin C and methotrexate. KCP-4 cells were not cross-resistant to doxorubicin, daunorubicin, vincristine or CdSO4. The accumulations of cisplatin in KCP-4 cells and PC-5 in medium containing 50 microM cisplatin were approximately 20% of those in the parental cells. Revertant analysis suggested that a defect in cisplatin accumulation may be related to cisplatin resistance in PC-5 cells. The uncoupling agent of oxidative phosphorylation, 2,4-dinitrophenol, increased the accumulation of cisplatin in KCP-4 and cisplatin-resistant human prostate carcinoma PC-5 cells to nearly the same level as in their parental KB-3-1 and human prostate carcinoma PC-3 cells without 2,4-dinitrophenol, but did not increase accumulation in KB-3-1 and PC-3 cells. Addition of glucose in the medium inhibited the enhancement of cisplatin accumulation in KCP-4 cells by 2,4-dinitrophenol. Enhanced active efflux of cisplatin from KCP-4 cells was observed. A cell-cell hybridization test showed that the cisplatin resistance and the accumulation defect behaved as codominant traits. These data suggest that an active efflux system for cisplatin exists in cisplatin-resistant KCP-4 cells.

Biological Transport, Active↗