In vitro assessment of nucleoside analogs in multiple myeloma

Purpose To identify nucleoside analogs that may be effective for multiple myeloma (MM), we tested fludarabine, clofarabine, arabinosylguanine, cytarabine, troxacitabine, and gemcitabine in MM cell lines.Methods We employed biologic and biochemical assays in MM cell lines to evaluate the clinical potential of these nucleoside analogs.Results Among these purine and pyrimidine nucleoside analogs, fludarabine, clofarabine and gemcitabine were the most potent. MM cell lines, resistant to commonly used chemotherapeutic agents for this disease, were more sensitive to gemcitabine with an IC₅₀ in the nanomolar range. The greater cytotoxicity of gemcitabine in MM cells was consistent with greater accumulation of gemcitabine triphosphate, the major cytotoxic metabolite of this drug. MM.1S cells accumulated >100 M gemcitabine triphosphate but accumulated <20 M of the other analogs as the respective triphosphates. In addition incubation with gemcitabine resulted in inhibition of DNA synthesis. Incubation with 25, 50 or 100 nM gemcitabine resulted in a dose- and time-dependent increase in the cell population with a subG₁ DNA content indicative of apoptosis.Conclusions These results suggest that gemcitabine is a potent nucleoside analog in MM cell lines including cell types resistant to other chemotherapeutic agents. The greater activity of gemcitabine compared to other analogs seems to be due to favorable metabolism of this agent.This work was supported in part by grants CA57629 and CA85915 from the National Cancer Institute, Department of Health and Human Services and a Translational Research Award #6506-00 from the Leukemia and Lymphoma Society of America. Steven T. Rosen is the Dr. Ralph and Marion Falk Research Trust Translational Researcher of the Lymphoma Society of America.     

Surgical resection deteriorates gemcitabine-induced leukopenia in pancreatic cancer

Background Gemcitabine hydrochloride (GEM) is one of the most effective chemotherapeutic agents for pancreatic cancer; however, factors affecting GEM-induced leukopenia have not been clarified yet. In the present study, we analyzed the relationship between patients backgrounds and GEM-induced leukopenia.Methods Thirty-eight patients with pancreatic cancer were analyzed for correlation between the dose of GEM and the blood leukocyte number. Moreover, we compared leukopenia in resected and non-resected patients.Results The incidence of grade 3 or 4 leukopenia was 25% in the non-resected patients, whereas equivalent leukopenia was observed in 57% of the resected patients (P = 0.048 by the ² test). The relative decrease in blood leukocytes induced by GEM administration was more severe in resected patients (41.3 ± 9.9%), as compared to non-resected patients (52.6 ± 16.0%; P = 0.023 by t-test).Conclusion In the present study, we found that the administration of GEM to patients after surgical resection caused more severe leukopenia, as compared to findings in non-resected patients. These data suggested that more frequent monitoring of the leukocyte count and prolonged intervals between GEM administrations are necessary for resected patients with pancreatic cancer.     

Gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are medically unsuitable for or who have failed cisplatin-based chemotherapy

Objective: To evaluate the efficacy and toxicity of gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are unsuitable for or who have failed cisplatin-containing chemotherapy.Patients and Methods: Thirty-one patients with advanced transitional cell carcinoma (TCC) of the bladder were scheduled to receive gemcitabine and vinorelbine chemotherapy. Twenty-one patients had received no prior chemotherapy and their creatinine clearance was below 50 ml/min (group 1), and the remaining 10 patients did not respond to previous cisplatin-containing chemotherapy (group 2).Results: In group 1, objective response rate was 47.6%, including 2 (9.5%) complete and 8 (38.9%) partial responses. In group 2, partial response was observed in 2 (20%) patients. The median survival time for patients in group 1 and 2 were 15 months (range 3–23) and 7 months (range 3–21), respectively. Grades 3 or 4 leukopenia developed in 16.1% of patients. Overall, 12.9% of the patients suffered from grade 3 nonhematologic toxicity.Conclusion: Our preliminary data indicate that the combination of gemcitabine and vinorelbine is active and well tolerated especially in patients with advanced TCC who are unsuitable for cisplatin-based chemotherapy.     

A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer

PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.     

Phase-II Trial Using Gemcitabine as Monochemotherapy in Patients with Metastasized Pancreatic Carcinoma

Summary BACKGROUND: The aim of this phase-II study was to evaluate the efficacy of gemcitabine monochemotherapy in patients with metastasized pancreatic carcinoma known to have a poor overall tumor response rate to chemotherapy in order to achieve an improvement in the quality of life. METHODS: In 28 patients with metastasized pancreatic carcinoma (mean age, 63.7 years; range, 37 to 77 years; sex ratio, 13 males, 15 females), systemic chemotherapy with gemcitabine (dose, 1000 mg/m²) was administered on day 1, 8 and 15. After one further week (day 29), the cycle was repeated. After each 2nd cycle, extension of tumor growth (restaging) including radiological imaging (ultrasound, computed tomography, plain film of the thorax) and laboratory analysis (tumor marker) was performed. Frequency, severity and spectrum of side effects were assessed according to WHO grading prior to each treatment. Quality of life was evaluated using standardized questionnaires. RESULTS: All in all, 106 chemotherapeutic cycles were administered in 28 patients (range, 1–18 cycles; mean, 3.78). While in no patient complete remission was observed, 2 out of 28 patients showed partial remission (7.2 %). In 11 out of 28 patients, stable tumor disease was detected (39.2 %). Fifteen out of 28 patients (53.6 %) showed progressive tumor growth. Four out of 28 patients lived longer than 1 year (1-year survival rate, 14.3 %). Side effects of the chemotherapy were only moderate. Only in 26 of 106 cycles (26.5 %), side effects were documented. Significant improvement in the quality of life was reported in 25 % of the treated patients. CONCLUSIONS: Chemotherapy using gemcitabine is a well tolerable treatment option with a minimal rate of side effects in the case of metastasized pancreatic carcinoma. However, overall response rate is low. Even considering the acceptable median survival time of 9.1 months most likely caused by second-line chemotherapy, optimization of gemcitabine monotherapy appears to be required using a combination with a further potential cytostatic drug.     

Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl Cancer Research Network

The purpose of this study was to evaluate the activity of single-agent gemcitabine in previously treated patients with carcinoma of unknown primary site. Between January 1997 and October 1998, 39 patients were enrolled in this multicenter Phase II trial performed in the Minnie Pearl Cancer Research Network. Twenty-seven patients (69%) had adenocarcinoma or poorly differentiated adenocarcinoma; 35 patients (90%) had previously received treatment with chemotherapy regimens containing both a platinum agent and a taxane. Only 21% of patients had ever responded to previous therapy. Gemcitabine 1000 mg/m² was administered intravenously on days 1, 8, and 15 of each 28-day course. Three of 36 evaluable patients (8%) had partial responses, and 9 patients (25%) had minor responses or stable disease with improved symptoms. The median time to progression for patients with partial responses or stable disease/improved symptoms was 5 months. Treatment was well tolerated, with uncommon grade 3 or 4 toxicity. Gemcitabine produced a low objective response rate in this refractory patient population, although approximately one-third of patients experienced symptomatic improvement. Treatment with gemcitabine was well tolerated. Because gemcitabine has activity against a variety of adenocarcinomas, further evaluation of this agent as part of first-line therapy for patients with carcinoma of unknown primary site is appropriate.     

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial

Background. Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. Methods. Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m², respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m², respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III–IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III–IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. Results. Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m² for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III–IV hematological or nonhematological toxicity. Conclusion. The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m² on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials. Received: January 29, 2001 / Accepted: September 13, 2001     

细胞毒药物(Gemcitabine)治疗人胰腺癌裸鼠胰腺原位移植癌的实验研究

目的 探讨细胞毒药物（Gemcitabine)对胰腺癌裸鼠原位移植模型（SOI）生长，转移的抑制作用。方法　SOI模型分为Ⅰ组（Gemcitabine 100mg/kg),Ⅱ组（Gemcitabine50mg/kg)和对照组。Gemcitabine于术后第2，3，6，9天给药，ip，术后第10周处死裸鼠；并对肿瘤组织的增殖指数（PI），凋亡指数（AI）以及PI/AI进行分析。结果 （1）Ⅰ组能显著抑制胰腺癌生长，Ⅱ组则无显著的肿瘤抑制作用，但两者对胰腺癌转移和预后均无显著疗效；（2）Ⅰ组可显著降低肿瘤增殖指数（PI），增大凋亡指数（AI），PI/AI显著降低。结论 Gemcitabine单用能有效抑制胰腺癌生长，但对肿瘤转移无显著抑制作用。     

Phase 2 Trial of Gemcitabine,Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Background

Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.