Bcl-2 antisense oligodeoxyribonucleotide increases apoptosis of lung carcinoma cells induced by cisplatin]

OBJECTIVE: To study the effect of antisense oligodeoxyribonucleotide (ODN) to apoptotic suppress gene bcl-2 on apoptosis of lung carcinoma cells induced by cisplatin. METHODS: The lung carcinoma cells expressing bcl-2 were chosen to participate in this experiment. Cultured cells were divided into 7 groups: ODN, nonsense, ODN + cisplatin, nonsense + cisplatin, cisplatin, lipofectin and control. Bcl-2 antisense or nonsense mixed with lipofectin was added into above corresponding cultured cells. After cultured for 6 hours, cisplatin was added into corresponding groups. The cells were cultured again for 16 hours. And then, the cells were smeared on slides. Apoptotic cells were labeled with TdT-mediated dUTP nick end labeling (TUNEL) method on cell smears. Apoptotic index (AI) was counted to show the percentage of apoptotic cancer cells. The immunocytochemistry was used to detect the expression of bcl-2 in carcinoma cells. RESULTS: The bcl-2 expression of cancer cell in ODN group was significantly decreased compared to the control and nonsense groups. The AI of ODN + cisplatin group was 16.4 +/- 1.7, cisplatin group 4.1 +/- 0.8, antisense group 5.9 +/- 0.2, nonsense group 3.3 +/- 0.7, nonsense + cisplatin 7.6 +/- 1.1, lipofectin 5.1 +/- 0.9, control group 3.6 +/- 0.6. The AI of antisense + cisplatin group was significantly higher than that of other groups. CONCLUSION: Antisense oligodeoxyribonucleotide to bcl-2 can inhibit significantly the expression of bcl-2 of lung cancer cells and increase apoptosis of cancer cells induced by cisplatin.     

Glucocorticoids enhance cytotoxicity of cisplatin via suppression of NF-{kappa}B activation in the glucocorticoid receptor-rich human cervical carcinoma cell line SiHa

Glucocorticoids (GCs) are commonly co-administered with cisplatin in the treatment of patients with carcinomas to prevent drug-induced allergic reaction, nausea and vomiting. Although GC receptor (GR) is ubiquitous in carcinoma cells and has been linked to signal transduction pathways pertinent to cell growth and apoptosis, little is known regarding the possible effect of GC on the chemosensitivity of carcinomas. Our previous study demonstrated that dexamethasone (DEX) enhances the cytotoxicity to cisplatin in a GR-rich human cervical carcinoma cell line, SiHa. In this study, we found that this cisplatin cytotoxicity-enhancing effect of DEX correlated well with its effect on abrogating the cisplatin-induced activation of nuclear factor kappa B (NF-kappaB). RU486, a structural homologue of DEX, partially reversed this cytotoxicity-enhancing effect of DEX, a finding consistent with the well-known partial reversing effect of RU486 on DEX-induced NF-kappaB suppression. Furthermore, expression of a dominant-negative truncated IkappaBalpha gene in SiHa cells completely abolished the cisplatin cytotoxicity-enhancing effect of DEX. Our data suggest that the specific action of DEX on GR may enhance the cytotoxicity of cisplatin in selected GR-rich cancer cells by suppressing NF-kappaB activation.     

Exposure of human ovarian carcinoma to cisplatin transiently sensitizes the tumor cells for liposome-mediated gene transfer.

Human ovarian carcinoma cells (line 2008) grown as subcutaneous solid tumor in the severe combined immunodeficient mouse can be transfected by directly injecting a plasmid DNA-liposome complex into the tumor (in situ lipofection). The level of reporter gene expression in the tumor cells was significantly elevated if the animal received a single i.p. injection of cisplatin 1 week before the lipofection. Sensitization of the tumor for lipofection peaked 1 week after cisplatin injection and declined thereafter. Cells exposed to low concentration of cisplatin in vitro for four to five doubling times also showed elevated sensitivity for lipofection in vitro. Cisplatin was the only anticancer drug tested that exhibited this activity. These results suggest a sequential combinational gene therapy protocol with cisplatin for the ovarian carcinoma.     

Complete regression of recurrent esophageal carcinoma with reduced expression of glutathione S-transferase-π by treatment with continuous infusion of 5-fluorouracil and low-dose cisplatin infusion

The mortality rate of recurrent esophageal carcinoma remains high because of its resistance to chemotherapy and radiation therapy. We present a patient with recurrent esophageal carcinoma, which dramatically disappeared after treatment with the combination of continuous infusion of 5-fluorouracil and low-dose cis-Diamminedichloroplatinum-II (cisplatin) infusion (FP therapy). Furthermore, we immunohistologically found that glutathione S-transferases (GST)-pi, a marker of resistance to cisplatin, was faintly expressed both in the endoscopical biopsy specimens of recurrent tumor and in the resected specimens of esophageal carcinoma and metastatic lymph nodes. FP therapy was suggested to be effective for recurrent esophageal carcinoma. Immunostaining for GST-pi might be a prospective marker for the sensitivity of esophageal carcinoma to FP therapy, particularly cisplatin.     

Cisplatin-induced autonomic neuropathy

A 57-year-old man with bronchogenic squamous cell carcinoma developed an autonomic neuropathy following treatment with a chemotherapy combination which included cisplatin. The autonomic neuropathy resolved following discontinuation of the cisplatin and treatment with dextroamphetamine. The following case represents a patient with bronchogenic carcinoma treated with cyclophosphamide, doxorubicin, and cisplatin, who developed a severe autonomic neuropathy following chemotherapy administration. This is the first report of cisplatin-associated autonomic neuropathy to appear in the literature.     

Bleomycin, mitomycin, and cisplatin therapy for advanced squamous carcinoma of the uterine cervix: a phase II study of the Northern California Oncology Group

Twenty-eight patients with advanced squamous carcinoma of the uterine cervix received cisplatin, bleomycin, and mitomycin after failure of surgery and/or irradiation to control disease. Six patients (21%) achieved responses (two complete; four partial), ranging from 3 to 7+ months. Toxicity was acceptable for most patients; however, dose reduction because of myelosuppression was frequently required. Bleomycin was delivered by continuous iv infusion, and no significant pulmonary toxicity was observed. Although this combination of drugs has activity in advanced squamous carcinoma of the uterine cervix, the addition of cisplatin to bleomycin and mitomycin did not significantly increase the clinical response rate.     

GRP78的表达非小细胞性肺癌细胞A549对顺铂的敏感性

目的探讨下调GRP78的表达后是否增强非小细胞性肺癌细胞对顺铂的敏感性。方法通过蛋白印记的方法检测内质网应激后GRP78的表达变化;用流式细胞仪检测用siRNAGRP 78抑制GRP 78的表达上调后凋亡细胞的数目;用A549肿瘤细胞对裸鼠进行了皮下荷瘤,在体内检验GRP78的表达水平对顺铂耐药的影响;运用免疫组织化学的方法检测肺癌患者的肿瘤组织中GRP78的表达水平。结果内质网应激能上调GRP78的表达;抑制内质网应激诱导的GRP78的表达上调后,细胞对顺铂的敏感性增加;将GRP78基因表达干扰后,荷瘤组织的生长明显受到顺铂的抑制;20例肺癌患者的肿瘤组织与癌旁组织相比,存在GRP78的高表达。结论 GRP78的表达水平上调降低非小细胞性肺癌细胞对顺铂的敏感性,具体的参与调控的信号通路需要进一步的机制研究。     

Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil

The therapeutic effectiveness of transcatheter arterial embolization (TAE) with intraarterial infusion of cisplatin/ethiodized oil mixture in treatment of resectable and unresectable hepatocellular carcinoma was compared with TAE with intraarterial infusion of doxorubicin mixed with and without ethiodized oil. The series included 97 patients with unresectable hepatocellular carcinoma and 40 patients with resectable hepatocellular carcinoma. With TAE using doxorubicin infusion, a partial response of the tumor was seen in only 11%, and the 2-yr survival was calculated to be only 5%. Histologic examination of the specimens obtained by hepatectomy also showed that this treatment was relatively ineffective in daughter tumor and portal tumor thrombi. In contrast, TAE with infusion of cisplatin/ethiodized oil mixture significantly increased the rate of partial response (38%), and significantly prolonged the 2-yr survival (45%). Histologically this treatment gave severe necrosis in daughter tumors (69%) and tumor thrombi (78%) as well as main tumor (75%). This treatment was significantly better than TAE with doxorubicin and ethiodized oil infusion in terms of the tumor regression and histologic responses of main tumor and portal vein tumor thrombi, but not in terms of the 2-yr survival. However, 2 patients (8%) died within 4 wk of the latter treatment, whereas no deaths were reported after the former treatment. Therefore, TAE combined with intraarterial infusion of cisplatin/ethiodized oil mixture may be a safe and useful treatment modality for hepatocellular carcinoma.     

Phase II study of cisplatin, maytansine, and chlorozotocin in small cell lung carcinoma (EST 2578)

Seventy-three patients with small cell lung carcinoma refractory to standard chemotherapy were entered in this phase II randomized study of cisplatin, maytansine, and chlorozotocin. Of the 58 evaluable patients, only one partial response was observed among 21 patients given cisplatin, and no responses were seen among 19 given maytansine or 18 given chlorozotocin. One patient treated with chlorozotocin and two treated with cisplatin experienced life-threatening thrombocytopenia. One third of the maytansine-treated patients experienced moderate or severe neurologic toxicity. The overall median survival was 9.7 weeks. Chlorozotocin treatment was associated with inferior survival (7.7 weeks).     

Suitable blending method of lipiodol-cisplatin in transcatheter arterial embolization for hepatocellular carcinoma: evaluation of sustained release and accumulation nature

BACKGROUND/AIMS: Recently, fine powder cisplatin (IA-call; Nipponkayaku, Japan) was released, but there is no detailed study on an appropriate blending method of lipiodol-cisplatin for transcatheter arterial chemoembolization. We evaluated the sustained release and accumulation nature of lipiodol-cisplatin for hepatocellular carcinoma. METHODOLOGY: We prepared three types of mixture: a suspension of lipiodol and cisplatin powder, an emulsion of cisplatin powder dissolved with contrast medium and lipiodol, and a suspension-emulsion that was a suspension of lipiodol and cisplatin powder emulsified with contrast medium. In a basic study, a cisplatin release test was performed. In a clinical evaluation, transcatheter arterial chemoembolization with 3 lipiodol-cisplatin mixtures that had sustained release was performed in 60 consecutive patients with hepatocellular carcinoma as a randomized controlled trial. The density ratio of the tumor and treated liver tissue was measured as the accumulation nature. RESULTS: The suspension-emulsion and emulsion with a 7:3 mixture of lipiodol and contrast medium, and the suspension had better sustained release. The accumulation nature of the suspension-emulsion and emulsion were higher than the suspension. CONCLUSIONS: The pattern efficiently accumulated on hepatocellular carcinoma was the suspension-emulsion and emulsion. We suggest that a suspension-emulsion may be created more easily and is more suitable for clinical use.     

Metastatic carcinoma of unknown primary: complete response to second-line treatment with plicamycin

In selected groups of patients, metastatic carcinoma of unknown primary (MCUP) is highly responsive to cisplatin-based combination chemotherapy. These therapeutic responses usually are partial and shortlived. The authors report the case of a 41-year-old man whose MCUP relapsed after responding to cisplatin, bleomycin, and etoposide. Alternate-day treatment with plicamycin induced a second complete remission (CR) in this patient with minimal hematologic and metabolic toxicity. Plicamycin may prove effective in enhancing CR rate, prolonging CR duration, and salvaging cisplatin failures in MCUP.     

Elevated expression of thymidylate synthase cycle genes in cisplatin-resistant human ovarian carcinoma A2780 cells.

Activity of the thymidylate synthase cycle was compared in the human ovarian carcinoma cell line A2780 and a subline that is resistant to cisplatin by a factor of 3. Resistant cells exhibited a 3-fold increase in mRNA for both dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+-oxidoreductase, EC 1.5.1.3) and thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) when compared with the parent line. Resistance to cisplatin also resulted in a 2.5-fold increase in enzyme activity for dihydrofolate reductase and thymidylate synthase; however, this increase did not result from amplification of the genes for these two enzymes. These data suggest that the initial step of cisplatin resistance in A2780 cells is a consequence of enhanced expression of the thymidylate synthase cycle.     

Phase II trial of cisplatin in small cell carcinoma of the lung

Eighteen patients with histologically documented small cell carcinoma of the lung who had failed initial combination chemotherapy regimens were treated with single-agent cisplatin in a dose of 100 mg/m2 every 3 weeks, with mannitol and fluid diuresis. Tumor regression was limited to one partial response (response rate, 6%; 95% confidence limits. 1%-27%). Significant toxic effects were gastrointestinal (severe nausea and vomiting in 12 of 14 patients) and hematologic (severe leukopenia in one patient and severe thrombocytopenia in three). The antitumor efficacy of high-dose cisplatin in heavily pretreated patients with small cell carcinoma of the lung appears to be marginal.     

Long-term survivor of gastric small cell carcinoma

We describe the long-term survival of a patient following the diagnosis of primary gastric small cell carcinoma. In January 2000, a 73-year-old male was found to have advanced gastric small cell carcinoma directly invading his liver. He received combination chemotherapy with cisplatin and irinotecan as first-line chemotherapy, then cisplatin and etoposide as second-line chemotherapy. He had a complete response after four cycles of second-line chemotherapy. In March 2001, the tumor recurred in the stomach and the patient underwent a total gastrectomy. He has survived free of disease for more than 2 years after the first diagnosis.     

吉西他滨联合顺铂对晚期肺鳞癌及肺腺癌治疗的临床疗效比较

目的观察吉西他滨联合顺铂的化疗方案对晚期肺鳞癌及肺腺癌的临床疗效及生存差异。方法肺鳞癌组47例及肺腺癌37例患者给予吉西他滨（1000mg／m2）联合顺铂（75mg／m。）化疗,每21天为一周期,共化疗4个周期。结果肺鳞癌组PR为14例（29．8％）,SD为21例（44．7％）,PD为12例（25．5％）,RR为29．8％,中位生存期为13个月,1年生存率为53．2％;肺腺癌组PR为10例（27．0％）,SD为18例（48．6％）,PD为9例（24．3％）,RR为27．0％,中位生存期为9个月,1年生存率为27．0％;结论吉西他滨联合顺铂对晚期肺癌及鳞癌的临床疗效相当,但肺鳞癌较肺腺癌具有较好的1年生存率及生存时间。     

Hsp90 inhibitor geldanamycin increases the sensitivity of resistant ovarian adenocarcinoma cell line A2780cis to cisplatin

Ovarian carcinoma is the leading cause of death among gynecological neoplasms in the world. The chemoresistance is a major obstacle in the effective treatment of ovarian and other cancers. We evaluated the effects of Hsp90 inhibitor geldanamycin (GEL) alone and in combination with cisplatin in cisplatin resistant ovarian adenocarcinoma cell line. Our results showed Akt depletion and S-phase arrest of A2780cis cells after GEL treatment. Combined exposure of A2780cis cells to GEL and cisplatin resulted in greater than additive cytotoxic effect.     

Synergistic growth inhibitory effects of Phyllanthus emblica and Terminalia bellerica extracts with conventional cytotoxic agents：Doxorubicin and cisplatin against human hepatocellular carcinoma and lung cancer cells

AIM： To examine the growth inhibitory effects of Phyllanthus emblica （P. emblica） and Terminalia bellerica （T. bellerica） extracts on human hepatocellular carcinoma （HepG2）, and lung carcinoma （A549） cells and their synergistic effect with doxorubicin or cisplatin. METHODS： HepG2 and A549 cells were treated with P. emblica and T. bellerica extracts either alone or in combination with doxorubicin or cisplatin and effects on cell growth were determined using the sulforhodamine B （SRB） assay. The isobologram and combination index （CI） method of Chou-Talalay were used to evaluate interactions between plant extracts and drugs. RESULTS： P. emblica and T. bellerica extracts demonstrated growth inhibitory activity, with a certain degree of selectivity against the two cancer cell lines tested. Synergistic effects （CI 〈 1） for P. emblica /doxorubicin or cisplatin at different dose levels were demonstrated in A549 and HepG2 cells. The T. bellerica/ cisplatin or doxorubicin also showed synergistic effects in A549 and HepG2 cells. In some instances, the combinations resulted in antagonistic effects. The dose reduction level was different and specific to each combination and cell line. CONCLUSION： The growth inhibitory activity of doxorubicin or cisplatin, as a single agent, may be modified by combinations of P. emblica or T. bellerica extracts and be synergistically enhanced in some cases. Depending on the combination ratio, the doses for each drug for a given degree of effect in the combination may be reduced. The mechanisms involved in this interaction between chemotherapeutic drugs and plant extracts remain unclear and should be further evaluated.     

Carboplatin: a new platinum analog in the treatment of epidermoid carcinoma of the esophagus

Thirty-one patients with advanced epidermoid carcinoma of the esophagus were treated with carboplatin (CBDCA), a second-generation cisplatin analog. Thirty patients were evaluable for response. Major responses (complete response) were seen in two patients (7%; 95% confidence limits, 1%-20%). The median survival from initiation of the protocol was 3 months (range, 0.1-16). Neither renal dysfunction nor emesis was a significant problem with CBDCA; hematologic toxicity was dose-limiting. Thrombocytopenia was more marked than leukopenia. CBDCA is a well-tolerated cisplatin analog that produced two complete responses in patients with advanced epidermoid carcinoma of the esophagus, where such responses are rarely observed. Although the observed response rate was only 7%, the 95% confidence limits overlap those previously reported for cisplatin (12%-31%).     

Cytokinetic effects of cisplatin on diverse human head and neck carcinomas in vitro: dependence on the tumor sensitivity to cisplatin

Studies performed with xenografted human head and neck carcinomas in vivo have demonstrated that the cytokinetic phenomena occurring under the influence of cisplatin closely correlate with the response of the tumors to therapy. The present paper analyses whether this correlation also exists in vitro. Four human head and neck carcinoma cell lines showing different degrees of sensitivity to cisplatin, as determined by the trypan blue exclusion assay, were investigated by flow cytometry at various intervals after administration of cisplatin. Early cell-cycle blockades in the S phase always reflected a high degree of cytostatic potency of cisplatin and were usually succeeded by a pronounced inhibition of tumor cell proliferation and a reduction of cell viability. In the case of a minimal response to therapy and in untreated control cultures of all four tumor lines, the relative number of S-phase cells continuously diminished during the observation period. These findings point to the S-phase blockade as the crucial cytokinetic effect of cisplatin preceding relevant growth reductions. This knowledge might support the development of a drugresponse assay that could predict the sensitivity of individual patient tumors in vitro before the beginning of clinical cancer chemotherapy.     

Neoadjuvant chemotherapy with a combination of irinotecan and cisplatin in advanced gastric cancer--a case report

We report a case of advanced gastric carcinoma successfully treated with a combination of irinotecan and cisplatin as neoadjuvant chemotherapy. The patient, a 78-year-old man, had type 2 gastric cancer, which had metastasized to the paraaortic lymph nodes. He was treated with irinotecan, 70 mg on day 1 and day 15, and cisplatin, 80 mg on day 1. The course was repeated every 4 weeks. Two courses of treatment resulted in a marked reduction of both the primary tumor and lymph nodes. Subsequently, the patient underwent curative surgery consisting of total gastrectomy, splenectomy, and D3 lymph node dissection. No surgical complications were observed. On microscopic examination, only a few tumor cells were detected in the granulation tissues of the resected stomach and in the lymph nodes. This would be the first case to demonstrate the effectiveness and the safety of irinotecan and cisplatin used in the neoadjuvant setting for treatment of advanced gastric carcinoma.