Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice

Purpose: The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth^®) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models. Methods: In therapeutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution study, mice received a single intravenous bolus injection of 3 mg/kg of either SPI-077 or cisplatin 14 days after inoculation with 10⁶ C26 tumor cells. Plasma and tissues were analyzed for total platinum (Pt) content by graphite furnace (flameless) atomic absorption spectrophotometery (GF-AAS). Results: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI-077 were compared to cisplatin at its maximally tolerated dose in Lewis lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold higher volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin. Conclusions: Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.     

Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer

To determine the efficacy and tolerability of SPI-77 (sterically stabilised liposomal cisplatin) at three dose levels in patients with advanced non-small-cell lung cancer (NSCLC). Patients had Stage IIIB or IV NSCLC and were chemo-naïve, and Eastern Oncology Cooperative Group 0–2. The first cohort received SPI-77 at 100 mg m⁻², the second 200 mg m⁻² and the final cohort 260 mg m⁻². Patients had also pharmacokinetics and analysis of leucocyte platinum (Pt)-DNA adducts performed. Twenty-six patients were treated, with 22 patients being evaluable for response. Only one response occurred at the 200 mg m⁻² dose level for an overall response rate of 4.5% (7.1% at ⩾200 mg m⁻²). No significant toxicity was noted including nephrotoxicity or ototoxicity aside from two patients with Grade 3 nausea. No routine antiemetics or hydration was used. The pharmacokinetic profile of SPI-77 was typical for a liposomally formulated drug, and the AUC appeared to be proportional to the dose of SPI-77. Plasma Pt levels and leucocyte DNA adduct levels did not appear to rise with successive doses. SPI-77 demonstrates only modest activity in patients with NSCLC.     

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer

Purpose: CPT-11 (60 mg/m² on days 1, 8 and 15) in combination with CDDP (80 mg/m² on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m² together with CDDP at 27 mg/m² (level 1, 6 patients), 33 mg/m² (level 2, 12 patients), and 40 mg/m² (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m² CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity. Received: 4 April 1997 / Accepted: 8 October 1997     

Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32 adult patients

Aims To develop a population pharmacokinetic model for simultaneous analysis of oral/intravenous cisplatin data in order to estimate the mean population pharmacokinetic parameters, mainly the bioavailability, of cisplatin and to evaluate the influence of covariates on the pharmacokinetic variability.Methods Pharmacokinetic and demographic data were collected from 32 adult patients (20 males/12 females, age range 47–76 years) receiving 30-min infusions or an oral formulation of cisplatin, 10–30 mg/m², for various malignancies. Both total plasma and ultrafilterable or unbound platinum concentrations were determined.Results Unbound and total platinum concentrations were ascribed to a two-compartment model, with first-order absorption and elimination. The oral bioavailability (F) population estimates were, respectively, 0.39 and 0.30 with associated intersubject variabilities (ISV) of 24% and 26%. Peak concentrations following oral dosing occurred at 1.0 h and 1.6 h for unbound and total platinum, respectively. Clearance (CL) and central distribution volume (V ₁) of unbound platinum were significantly related to body surface area (BSA). The CL and V ₁ mean estimates were, respectively, 37 l/h and 23 l with an associated ISV of 15%. The final pharmacokinetic models were validated using 1000 bootstrap samples of the original datasets.Conclusions Both unbound and total platinum data allowed a fair evaluation of oral cisplatin disposition, with close estimations for both absorption rates and oral bioavailability. These results also support the conventional dose adjustment of cisplatin based on BSA.     

重组人血管内皮抑素间插联合顺铂对H22小鼠腹水瘤抑制作用的研究

目的 观察重组人血管内皮抑制素（恩度）间插联合顺铂腹腔内注射治疗小鼠腹水瘤的疗效和安全性。方法 采用肝细胞癌H22腹水瘤细胞株建立小鼠腹水瘤模型。120只造模后的ICR小鼠随机分为4组：对照组（生理盐水d1～d10）、恩度组（恩度8mg／kg,d1～d5,d7～d10,生理盐水d6）、顺铂组（顺铂004mg／kg,d6,生理盐水d1～d5,d7～d10）及恩度联合顺铂组（恩度8mg／kg,d1～d5,d7～d10;顺铂0.04mg／kg,d6）,每组30只,每只小鼠腹腔注射的药物体积均为0.2ml。记录各组小鼠腹水体积、腹水中肿瘤细胞、红细胞计数以及生存期;观察各组荷瘤小鼠腹膜和腹腔脏器种植转移情况;检测各组小鼠的腹膜渗透性、血常规和肝肾功能;流式细胞仪检测各组小鼠腹腔积液中肿瘤细胞凋亡情况。结果 与对照组相比,恩度组和顺铂组和恩度联合顺铂组均能减少荷瘤小鼠腹腔积液的体积、肿瘤细胞数和红细胞数,延长荷瘤小鼠的生存时间。在上述指标中,恩度联合顺铂组与恩度组和顺铂组比较,差异有统计学意义（P＜0.05）。恩度联合顺铂组小鼠腹腔积液中肿瘤细胞的凋亡率显著高于恩度组和对照组（P＜0.05）,但与顺铂组比较差异无统计学意义（P＞0.05）;恩度联合顺铂组小鼠的腹膜渗透性明显低于顺铂组和对照组（P＜0.05）,但恩度联合顺铂组与恩度组比较差异无统计学意义（P＞0.05）。恩度联合顺铂组小鼠的体重增加及腹腔种植转移均少于其他3组。各组小鼠均未出现血常规和肝肾功能明显异常。结论 恩度间插联合顺铂腹腔内应用治疗小鼠H22腹水瘤疗效显著,安全性好。     

Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer.

Background:Concomitant chemoradiotherapy (CCRT) for squamous cancers of the head and neck (SCCHN) improves survival but increases toxicity. Pegylated liposomes localise to solid cancers and may deliver radiosensitizing agents preferentially to tumour tissue, potentially improving the therapeutic ratio of CCRT. Patients and methods:A phase I–II trial of pegylated liposome encapsulated cisplatin (SPI-077^TM) was conducted in 18 patients with treatment-naïve locally advanced, inoperable SCCHN. The first 10 patients received 2 cycles of 200 mg/m², and the next 8 received 260 mg/m², every 3 weeks before commencing radical radiotherapy (RT). Results:Only 2 of 18 (11%) patients had partial responses to SPI-077^TM, with 2 responses in 29 (6.9%) evaluable sites. SPI-077^TM was tolerated well with no haematological, renal, hepatic or neurological toxicities. Nausea and vomiting were minimal. There were no drug-related delays in the delivery of RT. RT-induced mucosal and cutaneous toxicity were not significantly increased. Conclusions:SPI-077^TM is essentially inactive against SCCHN and, in its present formulation, does not merit further evaluation as induction chemotherapy or as part of a CCRT approach.     

Kinetics of tissue disposition ofcis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin in mice bearing FSallC tumors

The clinical potential of mixed amine platinum(IV) complexes has been identified, and interest in this new class of antitumor agents has been heightened by demonstration of their activity in cisplatin-resistant neoplasms. These tetravalent platinum agents are expected to undergo a reductive reaction to form the corresponding platinum(II) drug prior to eliciting biological activity.cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such product that we evaluated with cisplatin in vivo, and we found the two complexes given i.v. or i.p. to have comparable activities against a solid murine fibrosarcoma. Following i.v. administration of the two compounds at equitoxic dose levels (20 mg/kg) to tumor-bearing mice, platinum levels in the plasma were consistently higher for cisplatin. Tissue platinum levels, in contrast, were comparable between the agents or higher for the mixed amine analog at the earliest (3-h) time point. The temporal profiles determined for the concentrations over 48 h were tissue-and/or drug-specific and could be described by terminalphase constants or half-lives of platinum in most tissues. In the plasma, kidney, lung, and jejunum, platinum levels arising from both compounds decayed with half-lives of 24–92 h. The terminal-phase constants of platinum determined in the heart for the two complexes were not significantly different from zero, indicative of levels remaining steady, whereas the constants were negative in the spleen, indicative of an increase in tissue drug concentration. In the tumor, liver, and testes, positive values for the decay-phase constants corresponding to half-lives of 47, 256, and 79 h, respectively, were seen with the mixed amine complex; this pattern contrasted with that found for cisplatin, for which the terminal-phase constant was either zero or negative. In vitro binding studies demonstrated the mixed amine complex to be more reactive. Thus, the presence of one ammine and one cyclohexylamine carrier ligand in the mixed amine complex, as opposed to the diammine ligands in cisplatin, leads to an increase in drug distribution and an alteration in the kinetics of tissue binding and removal of platinum.Abbreviations DACH 1,2-Diaminocyclohexane - FAAS flameless atomic absorption spectrophotometry - FBS fetal bovine serum     

Comparison of the in vitro and in vivo effects of retinoids either alone or in combination with cisplatin and 5-fluorouracil on tumor development and metastasis of melanoma

Purpose  Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model. Methods  Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin. Results  Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13-cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice. Conclusion  These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo.     

Biliary excretion of platinum in rats after administration of cisplatin and aqua(1,1-bis(aminomethyl)-cyclohexane)sulfatoplatinum(II) (spiroplatin, TNO-6)

Three groups of 6 rats were treated with cisplatin (3 mg/kg, bolus and 3-h infusion) and spiroplatin (3 mg/kg, bolus) by infusion in the right external jugular vein. The mean amounts of platinum +/- c.v. excreted in the bile during the first 6 h after the start of administration were 0.32 +/- 0.19% and 0.39 +/- 0.29% of the dose after bolus injection and 3-h infusion of cisplatin, respectively, and 3.77 +/- 3.32% of the dose after spiroplatin. The values were not significantly different between the 2 cisplatin administration modes (P greater than 0.05), but were between the spiroplatin and cisplatin bolus groups (Wilcoxon two-sided rank test, P less than 0.01). These data are related to pharmacokinetic parameters in man.     

A Comparison of 3 tumor markers (MIA, TA90IC, S100B) in stage III melanoma patients

Purpose: There is no consensus regarding the optimal tumor markers for melanoma. We compared 3 tumor markers, TA90-immune complex (TA90IC), melanoma-inhibiting activity (MIA) protein, and S100B protein in Stage III melanoma patients undergoing adjuvant vaccine immunotherapy. Experimental design: The serum of 75 patients representing 3 prognostic cohorts was assayed for the tumor markers prior to initiating immunotherapy and at 6 follow-up time points. Upper limits of normal for TA90IC, MIA and S100B were set at OD 0.41, 8.5 ng/ml, and 2.5 μ g/l, respectively. Results: At least 1 marker became elevated prior to 41 (80 percent) of 51 recurrences. TA90IC was the earliest elevated marker in 29 (57 percent), MIA in 11 (22 percent), and S100B in 4 (8 percent). Multivariate regression analysis revealed that TA90IC was an independent predictor of survival when elevation occurred between 2 weeks and 3 months, whereas MIA was an independent predictor at 4-6 months. In the poor prognostic cohort, mean values for MIA and S100B increased progressively, whereas TA90IC exhibited a parabolic curve. Conclusion: In this patient population, TA90IC and MIA were complementary; elevation of the immune complex preceded elevation of the tumor antigen in patients who developed recurrence. Additional studies in populations not receiving vaccine will further clarify the clinical utility of these assays.     

Activity and safety of a low dose,fractional administration of irinotecan hydrochloride (CPT-11) in combination with cisplatin for relapsed gastric cancer patients: a preliminary report

Background: Irinotecan hydrochloride (CPT-11) in combination with cisplatin has emerged as a new therapeutic option for the treatment of advanced gastric cancer. So far, very few combination trials have been reported, and a relatively high frequency of grade 3/4 toxicities in previous trials has been a major problem. The purpose of this study was to elucidate the efficacy and safety of a low dose, fractional administration of CPT-11 and cisplatin that is principally based on recently acquired knowledge of the synergistic antitumor activities between these two agents. Methods: Five relapsed gastric cancer patients were treated every 2 weeks with a starting dose of CPT-11 (30 mg/m²) and a fixed dose of cisplatin (30 mg/m²). All patients were of performance status 0 and had received prior chemotherapy. Dose escalation of CPT-11 to 40 mg/m² or to 50 mg/m² was performed whenever possible. Responses, toxicities, and at-home ratio during chemotherapy were evaluated. Results: The response rate reached 40%. Toxicities were grade 1/2, and no grade 3/4 hematological toxicities or diarrhea were observed. Repeated subsequent treatments could be performed in an outpatient setting without treatment delay or cancellations, which resulted in an 83%–92% at-home ratio in four patients receiving five or more cycles of treatment. There were no treatment-related deaths. Conclusion: A low dose, fractional administration of CPT-11 and cisplatin seems rational, encouraging, and safe, and compares well with other trials of the combination. Outpatient administration provides the patients with a better quality of life, suggesting a meaningful therapeutic option for relapsed gastric cancer patients in particular. Received: June 6, 2002 / Accepted: December 2, 2002 Correspondence to:S. Shimoyama     

The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates

PURPOSE: Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. METHODS: Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). RESULTS: Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. CONCLUSIONS: Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.     

Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice

The antitumor efficacy of the CK2 inhibitors so far described has not been extensively evaluated in cancer animal models. We have previously demonstrated that a proapoptotic cyclic peptide termed P15 delivered into the cells by the Tat Cell Penetrating Peptide was able to abrogate the CK2-mediated phosphorylation and induce tumor regression when injected directly into solid tumors in mice. Here we explored the antitumor effect by systemic administration of P15-Tat in a consecutive 5-day schedule through either intraperitoneal or intravenous route. Importantly, significant delay of tumor growth was observed at 2 mg/kg (p < 0.05), 10 mg/kg (p < 0.01) or 40 mg/kg (p < 0.001) after P15-Tat administration both in syngeneic murine tumors and human tumors xenografted in nude mice. In line with this, the systemic administration of P15-Tat induced apoptosis in the tumor as evidenced by in situ DNA fragmentation. Furthermore, we evidenced that 99mTc-labeled P15-Tat peptide was certainly accumulated on the tumors after administration by both routes. This report becomes the first describing the antitumor effect induced by systemic administration of a peptide that targets the acidic phosphorylation domain for CK2 substrates. Also, our data reinforces the perspectives of P15-Tat for the cancer targeted therapy.     

Alphastatin-C a new inhibitor of endothelial cell activation is a pro-arteriogenic agent in vivo and retards B16-F10 melanoma growth in a preclinical model

Most characterized angiogenic modulators are proteolytic fragments of structural plasma and/or matrix components. Herein, we have identified a novel anti-angiogenic peptide generated by the in vitro hydrolysis of the C-terminal moiety of the fibrinogen alpha chain, produced by the snake venom metalloprotease bothropasin (SVMP), a hemorrhagic proteinase in Bothrops jararaca venom. The 14-amino acids peptide (alphastatin-C) is a potent antagonist of basic fibroblast growth factor, induced endothelial cell (HUVEC-CS) proliferation, migration and capillary tube formation in matrigel. It also inhibits cell adhesion to fibronectin. The basis of the antagonism between bFGF and alphastatin-C is elucidated by the inhibition of various bFGF induced signaling pathways and their molecular components modification, whenever the combination of the stimuli is provided, in comparison to the treatment with bFGF only. To corroborate to the potential therapeutic use of alphastatin-C, we have chosen to perform in vivo assays in two distinct angiogenic settings. In chick model, alphastatin-C inhibits chorioallantoic membrane angiogenesis. In mouse, it efficiently reduces tumor number and volume in a melanoma model, due to the impairment of tumor neovascularization in treated mice. In contrast, we show that the alphastatin-C peptide induces arteriogenesis, increasing pial collateral density in neonate mice. alphastatin-C is an efficient new antiangiogenic FGF-associated agent in vitro, it is an inhibitor of embryonic and tumor vascularization in vivo while, it is an arteriogenic agent. The results also suggest that SVMPs can be used as in vitro biochemical tools to process plasma and/or matrix macromolecular components unraveling new angiostatic peptides.     

The influence of time sequence of cisplatin administration and continuous low dose rate irradiation (CLDRI) on their combined effects on a murine squamous cell carcinoma

The influence of time sequence of cis-dichlorodiammine platinum (cisplatin) administration and continuous low dose rate irradiation (CLDRI) on their combined effects was studied in the SCC VII/SF tumor, a murine squamous cell carcinoma. Concurrent cisplatin i.p. infusion at 0.22 mg/kg/hr and CLDRI at 0.6 Gy/hr had a supraadditive effect on the survival of the SCC VII/SF tumor cells. Cisplatin by itself was more effective against the SCC VII/SF tumor when given by bolus injection than by continuous infusion i.p. However, when cisplatin at a dose of 6 mg/kg was given by bolus i.p. injection either immediately before or after CLDRI, the combined effects on the SCC VII/SF tumor cell survival were no more than additive. Exposure to CLDRI at 0.6 Gy/hr for 24 hours did not sensitize the SCC VII/SF tumor to subsequent treatment with cisplatin. These results suggest that when cisplatin is combined with CLDRI, for the optimal anti-tumor effect, it is best to infuse the cisplatin continuously during the course of CLDRI.     

A multicenter phase II study of cisplatin and docetaxel (Taxotere) in the first-line treatment of advanced ovarian cancer: a GINECO study

Purpose A multicenter phase II study to evaluate the antitumor effect and safety of docetaxel in combination with cisplatin as first-line chemotherapy for advanced ovarian cancer.Methods Enrolled in the study were 45 patients who were to receive six courses of docetaxel 75 mg/m² plus cisplatin 75 mg/m² every 21 days with hydration and steroid prophylaxis after initial debulking surgery. Imaging techniques and radiography were used to assess clinical tumor response, and second-look surgery was required for patients with complete clinical responses and for those without clinically measurable disease.Results The overall clinical response rate in 29 patients with clinically measurable disease was 58% (41% complete response). A complete pathologic response was seen in 9 of 34 patients who underwent second-look laparotomy, while microscopic disease was found in 10 patients. The median time to progression was 14.4 months (95% CI 8.4–20.4 months), with a median overall survival of 43 months (95% CI 21.1–65.0 months). Patients received a median number of six cycles at a dose intensity of 98%. Grade 3–4 neutropenia was seen in 80% of patients, but was manageable. No patients withdrew because of fluid retention.Conclusions The combination of docetaxel with cisplatin confers high clinical and pathologically verified tumor response rates and is well tolerated in the first-line management of advanced ovarian cancer.     

细胞周期蛋白B1在肿瘤细胞中的非时相性表达

目的 证实细胞周期蛋白B1（cyclin B1）在体内和体外生长的肿瘤细胞中的非时相性周期表达模式,研究cyclin B1在不同生长状态和条件下的C1期肿瘤细胞中的表达情况。方法 以MOLT－4细胞为对照,应用流式细胞术的DNA/cyclin双参数分析法,检测体内和体外生长的肿瘤细胞中G1期cyclin B1的表达,对分选出的G1期细胞,以共聚焦显微镜观察G1期cyclin B1的表达;在不同体外生长情况下分选出G1期内亚细胞群体,以免疫印记法检测cyclin B1的表达。结果 在被阻滞生长的MOLT－4细胞、转化的T7细胞以及体内生长的肿瘤细胞中,均发现G1期有cyclin 的非时相性表达,被药物阻断生长的MOLT－4细胞中,cyclin B1主要表达于G1晚期;而转化的T7细胞中,cyclin B1主要表达于G1早期。结论 在研究的不同细胞模型中,G1期细胞有cyclin B1的非时相性表达,cyclin B1可以在G1期的不同时间点被检测到。这一现象可能与细胞的失控性增殖和细胞凋亡的调控之间有密切联系。     

Combination of topotecan and cisplatin in relapsed patients with small cell lung cancer: a phase II study of the hellenic cooperative oncology group (HeCOG)

Purpose: To assess the safety and efficacy of a 3-day schedule of cisplatin and topotecan in patients with recurrent small-cell lung cancer (SCLC). Methods: Thirty-four relapsed patients were treated with cisplatin 20 mg/m² and topotecan 0.9 mg/m², both given on days 1–3 every 3 weeks, in a phase II study. Results: Complete response (CR) was achieved in two patients (6%), partial response (PR) in 4 (12%), stable disease in 6 (18%) and progressive disease in 14 (41%). Eight patients (23%) were non-evaluable for response. Among 21 sensitive patients, 2 (9.5%) achieved CR and 3 (14%) PR. Among 13 refractory patients, none achieved CR and only 1 (8%) PR. Median survival was 6.5 months for all patients, 7.8 for sensitive and 6.2 for refractory. Median time to progression (TTP) was 4.4 months for all patients, 5.9 for sensitive and 3.2 for refractory. Grade 3–4 toxicities included anemia (15%), thrombocytopenia (15%), neutropenia (42%), nausea/vomiting (3%), and alopecia (6%). No toxic death occurred. Conclusions: This 3-day schedule was well tolerated, produced modest response rates but good survival and TTP both in sensitive and refractory patients with relapsed SCLC.     

Bleomycin-induced pulmonary fibrosis after tumor lysis syndrome in a case of advanced yolk sac tumor treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy

Ovarian yolk sac tumor (YST) is a highly aggressive malignancy arising in young women. Chemotherapy has dramatically improved the prognosis, and bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy appears to be the most effective combination regimen. A 23-year-old woman was admitted to our hospital with worsening abdominal distention and a lower abdominal mass. She was diagnosed with a stage IIIc pure YST of the right ovary, and right salpingo-oophorectomy was performed; there were numerous disseminated peritoneal tumors within the abdominal cavity. A few days postoperatively, massive ascites developed, and right hydronephrosis occurred. Chemotherapy with BEP was started, and after 24?h of administration, oliguria and tumor lysis syndrome (TLS) developed. Continuous hemodiafiltration was started, and hemodialysis was initiated following full-dose standard cisplatin and etoposide on days 2-5 of the 1st cycle. After the electrolyte abnormalities and the elevation of creatinine became normal, the patient received an additional three cycles of BEP and achieved complete remission. However, she also suffered from severe non-hematological toxicities, including grade 3 left ventricular dysfunction and grade 4 pulmonary fibrosis. In the case of rapidly progressing and high-volume YST treated with BEP chemotherapy, special attention should be paid to bleomycin-induced pulmonary toxicity following TLS. Further study is required to optimize drug exposure to ensure efficacy and reduce the risk of side effects in this population.