Administration in a hypotonic solution is preferable to dose escalation in intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in rats.

An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic solutions of sodium chloride has been developed as a treatment for peritoneal carcinomatosis. The concentrations of platinum in the plasma and in the i.p. fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154 mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of cisplatin. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) of platinum in the plasma increased proportionately with increases in the dose of cisplatin and they were significantly higher in rats given cisplatin in hypotonic solutions than in those given the drug in isotonic solution. The Cmax and AUC of total platinum were similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the plasma did not increase with increases in the dose of cisplatin in isotonic solution but did increase after hypotonic injection. However, the solutions of lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic conditions continued for 30 min at most after i.p. injection of hypotonic solutions. When the same dose of cisplatin was given to rats with tumors derived from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors from the solution of 103 mosm/l was about twice that from the isotonic solution and was much the same as that taken up from the isotonic solution with twice the amount of cisplatin. These results indicate that hypotonic i.p. cisplatin chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in the treatment of peritoneal carcinomatosis.     

Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer

Background  

Gastric cancer peritoneal carcinomatosis is a common clinical problem, but there are no suitable large animal models to study this problem. This study was to establish a stable rabbit peritoneal carcinomatosis model of gastric cancer using VX2 tumor, and analyze the clinico-pathological features.     

Treatment of peritoneal carcinomatosis in patients with digestive cancers with combination of intraperitoneal hyperthermia and mitomycin C

Peritoneal carcinomatosis in patients with digestive cancer carries a poor prognosis, with a majority of patients dying within 6 months. Mitomycin C has been reported to have some antitumor efficacy in this setting. We performed combination intraperitoneal hyperthermia and mitomycin to potentiate the effect of mitomycin C in 83 patients with peritoneal involvement due to digestive cancers. Eighty six IPCH procedures were performed using inflow temperature 46 to 49 degrees Celsius, using a closed circuit, during 90 minutes. Mitomycin C was administered as a perfusate at 10 mg/l. Primary tumors were essentially gastric (42) and colorectal (27). Mortality and morbidity rates were 3/83 and 5/83 respectively. For resectable tumors, the median survival time was 16 months in stage 1 and 2 carcinomatosis (malignant granulations less than 5 mm in diameter). For resectable gastric cancers with stage 1 and 2 carcinomatosis, one, two and three year actuarial survival rates were 80, 61 and 41% respectively. In conclusion, IPCH appears to be an interesting therapeutic option in patients with digestive cancers and small malignant peritoneal granulations (stage 1 and 2).     

Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis

Angiopoietin-1 is an important regulator of endothelial cell survival. Angiopoietin-1 also reduces vascular permeability mediated by vascular endothelial growth factor. The effects of angiopoietin-1 on tumour growth and angiogenesis are controversial. We hypothesised that angiopoietin-1 would decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control) or vector containing angiopoietin-1 and injected into the peritoneal cavities of mice. After 30 days, the following parameters were measured: number of peritoneal nodules, ascites volume, and diameter of the largest tumour. Effects of angiopoietin-1 on vascular permeability were investigated using an intradermal Miles assay with conditioned media from transfected cells. Seven of the nine mice in the pcDNA group developed ascites (1.3+/-0.5 ml (mean+/-s.e.m.)), whereas no ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.     

Intraperitoneal treatment using taxol is effective for experimental peritoneal carcinomatosis in a rat model

Following resection of colorectal carcinoma, a considerable local recurrence rate within the previous tumor bed or at the peritoneal site remains an unsolved problem. Currently, there are no established protocols for the treatment or prevention of peritoneal carcinomatosis. Taxol showed benefit in patients with advanced tumor growth, in particular, gynecological carcinomas. Taxol was used to test whether it can either prevent or treat peritoneal tumor growth derived from colon carcinoma. In rats divided in 3 groups, peritoneal carcinomatosis was induced by tumor cell transfer: Taxol (170 mg/m(2)) was given i). directly (group A); ii). on days 5, 10, 15 postoperatively (representing early administration; group B), or iii). as late intraperitoneal (i.p.) chemotherapy (15, 20, 25 days following surgery; aiming for reduction of a manifest peritoneal carcinomatosis; group C) into the abdominal cavity. Tumor growth was quantified by tumor weight of the greater omentum and the mesenteric site, number of detectable tumor lesions, occurrence of hepatic and pulmonary metastases and the amount of ascites. Taxol was highly effective in preventing or reducing i.p. tumor spread when the drug was given directly or within a short time interval after tumor cell implantation (groups A and B), whereas no significant antineoplastic potential was found in the treatment of an established peritoneal carcinomatosis. In conclusion, Taxol appears to be a promising chemotherapeutic agent to be investigated in further detail with possible potential for a later human phase-I trial in peritoneal carcinomatosis.     

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer

The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.     

热疗联合腹腔内灌注顺铂与胸腺五肽治疗恶性腹水的临床观察

目的 观察全身热疗联合腹腔内灌注顺铂与胸腺五肽治疗恶性腹水的临床疗效与安全性。方法 79例恶性腹水患者随机分为3组,顺铂组（A组,n=26例）予腹腔内灌注顺铂治疗;顺铂联合热疗组（B组,n=26例）予腹腔内灌注顺铂后30 min行全身热疗;顺铂与胸腺五肽联合热疗组（C组,n=27例）予腹腔内灌注顺铂和胸腺五肽混合液,30 min后行全身热疗。1周为1个疗程,共4个疗程,1周后复查并判定疗效。结果 C组的总有效率为77.80%,KPS评分提高率为85.19%,明显高于A组的42.30%、46.15%和B组的61.50%、69.23%,差异均有统计学意义（P均＜0.05）;B组与A组比较差异亦有统计学意义（P＜0.05）。C组毒副反应发生率为48.15%,与A组（53.85%）和B组（50.00%）比较差异均无统计学意义（P均＞0.05）,A组和B组比较差异亦无统计学意义（P＞0.05）。结论 全身热疗联合腹腔内灌注顺铂与胸腺五肽治疗恶性腹水临床效果良好,可改善患者生活质量。     

健择联合顺铂腹腔区域性热化疗治疗原发性肝细胞癌的临床研究

目的:研究健择联合顺铂进行腹腔区域性化疗治疗原发性肝细胞癌的疗效,寻找合适的原发性肝细胞癌的内科治疗方法。方法:实验组分别选择静脉应用健择联合腹腔灌注顺铂结合体外射频热疗,对照组静脉应用吡柔比星联合腹腔灌注顺铂对原发性肝细胞癌进行化疗,比较治疗效果。结果:实验组的有效率和临床获益率均明显高于对照组(P<0.05,P<0.01);实验组的生活质量评分明显优于对照组(0.01相似文献   

Enhanced therapeutic efficacy of cisplatin by combination with diethyldithiocarbamate and hyperthermia in a mouse model

A spontaneously metastasizing solid tumor model derived by transplanting the TA3Ha murine mammary carcinoma into the s.c. tail tissue of mice was used to develop a treatment strategy for enhancing the therapeutic efficacy of cisplatin (CDDP). This strategy was based on the findings that diethyldithiocarbamate (DDTC) reduces the toxicity of CDDP, and that localized hyperthermia (HT) augments the antitumor efficacy of CDDP. DDTC (500 mg/kg) reduced the CDDP-induced nephrotoxicity and gastrointestinal toxicity as well as increased the CDDP LD10 from 8 to 20 mg/kg in strain A mice. When CDDP and DDTC were used in multiple treatment schedules at 5-day intervals, DDTC protected the hosts but not the tumors against the toxicity of CDDP. HT administered locally to the tumor 1 h after the injection of CDDP (8 mg/kg) in 1 ml Hanks' balanced salt solution increased the antitumor effect but not the host toxicity. While administration of 8 mg/kg CDDP alone or with HT three times at 5-day intervals caused 100% host mortality, this dose of CDDP could be used with no mortality by combining it with DDTC. A combination of 8 mg/kg CDDP with DDTC (750 mg/kg) and HT (43 degree C for 60 min), administered three times at 5-day intervals, retarded the local tumor growth significantly compared to the untreated, CDDP plus DDTC plus HT control groups of mice. The frequency of lung metastasis in these groups on day 30 of tumor inoculation were 0, 90, 90, and 80%, respectively. The mean survival days of the mice treated with CDDP plus DDTC plus HT was 61 +/- 6 compared to 34 +/- 5 in the controls. The results presented here demonstrate that by combining CDDP with DDTC, high doses of CDDP can be safely administered. When localized HT is combined with high dose CDDP and DDTC, the tumor growth retardation and the host survival prolongation are significantly better than those obtained with the highest tolerable dose of CDDP alone or CDDP plus HT.     

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer

Background:

Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC.

Methods:

Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS).

Results:

The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8±10.4 μg ml⁻¹ and 69.8±14.3 μg ml⁻¹; in plasma were 1.87±0.4 μg ml⁻¹ and 0.055±0.009 μg ml⁻¹. The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3±8.0 μg g⁻¹ and 30.1±18.3 μg⁻¹g⁻¹, respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3–4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications.

Conclusions:

HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity.     

Effects of natural polysaccharides on the growth and peritoneal carcinomatosis of human gastric adenocarcinoma in a nude mouse model

We have examined the effects of natural polysaccharides isolated from Phellinus gilvus (PG) in vitro and in vivo against gastric cancer. PG decreased cell proliferation and increased cell apoptosis in a dose-dependent manner in vitro. PG also led to a marked inhibition of tumor growth and significant decrease in the incidence of peritoneal carcinomatosis. Histological analysis of tumor confirmed dramatic increase in tumor cell apoptosis by PG, indicating reduced tumor cell proliferation. These data showed that polysaccharides isolated from PG significantly inhibited tumor growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects.     

Pegylated liposome-encapsulated doxorubicin and cisplatin enhance the effect of radiotherapy in a tumor xenograft model.

Concomitant chemotherapy and radiotherapy (CCRT) has recently been shown to improve treatment outcome in a range of solid tumors. Pegylated liposomes have the potential to target drugs directly to tumors and may increase the efficacy and reduce the toxicity of CCRT by selectively delivering radiosensitizing agents to tumor, as opposed to normal, tissues. In these studies, we have assessed CCRT using pegylated liposome encapsulated doxorubicin (PLED) and pegylated liposome encapsulated cisplatin (PLEC) against KB head and neck cancer xenograft tumors in nude mice. The addition of low-dose (2 mg/kg) PLED (P < 0.001) and PLEC (P < 0.001) significantly increased the effect of 4.5 Gy, but not 9 Gy, single-fraction radiotherapy (SFRT). Both PLED and PLEC were significantly more effective than their unencapsulated counterparts in increasing the effect of SFRT. In addition, PLED (P < 0.001) and PLEC (P < 0.05) significantly increased the effect of fractionated radiotherapy (9 Gy in 3 fractions) in two different dosing schedules (2 mg/kg single dose or three sequential doses of 0.67 mg/kg). Unencapsulated diethylenetriaminepentaacetic acid and pegylated liposomal diethylenetriaminepentaacetic acid were used as controls to test the effect of the liposome vehicle and showed no interaction with 4.5 Gy or 9 Gy SFRT (P > 0.1). CCRT was well-tolerated, with no evidence of increased local or systemic toxicity, as compared with radiotherapy alone. This study is the first to demonstrate the value of pegylated liposomes as vehicles for the delivery of radiosensitizing drugs in CCRT strategies.     

Comparison of response to radiation, hyperthermia and cisplatin in parental and polymerase beta knockout cells.

The role of polymerase beta in response to radiation, cisplatin and hyperthermia was examined in a pair of mouse cell lines, comprising a normal parental line and a derivative with polymerase beta knockout. Cell survival was assessed using the colony survival assay. For irradiation, there was no difference in response between the two cell lines. Treatment with cisplatin for 1 h showed a large increase in resistance in the mutant cell line. The results with hyperthermia were more complex. The mutant was more resistant to 45 degrees C heating, but was slightly more heat sensitive than the wild type at 41 degrees C. Thus, in summary, while the knockout of polymerase beta did not alter radiation sensitivity, it did increase resistance to cisplatin and induced resistance to hyperthermia at higher temperatures (45 degrees C).     

Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis.

AIMS: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. METHODS: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdominopelvic cavity for 90 min, at a temperature of 41.5-42.5 degrees C, with mitomycin C (3.3 mg/m2/l) and cisplatin (25 mg/m2/l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m2) (for colonic or appendicular tumours) or cisplatin (25 mg/m2) (for ovarian tumours), each day for 5 days. RESULTS: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. CONCLUSIONS: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.     

Complications and tolerance of heated intraperitoneal chemotherapy and cytoreductive surgery for peritoneal carcinomatosis: results of a phase I-II study of peritoneal carcinomatosis from different sources

Peritoneal carcinomatosis represents the terminal stage of adenocarcinomas of the gastrointestinal tract. A new treatment combining cytoreductive surgery and intraperitoneal chemotherapy-hyperthermia has been used with encouraging results. The purpose of this study was to report the complications associated with this treatment. Fourty procedures were carry out in 37 patients. Death occurred in 3 patients. Major medical complications were 13 pulmonary infections, 11 acute renal failure (with only 3 who needed dialysis) and 10 patients with neutropenia grade 3 and 4 toxicity. Intra-abdominal complications occurred in 16 patients (there were 11 anastomotic leak and/or bowel perforation, and 12 intra-abdominal infections). Some complications like secretory diarrhea or tubulopathia which were related to these treatment need further investigations. Six procedures were without any complications, 6 presented minor ones and 22 major complications. Adverse effects were relatively important with this new treatment strategy. This was maybe due to a learning process; there is no death and only one anastomotic leak in our last study including 30 patients with cytoreductive surgery and intraperitoneal chemotherapy-hyperthermia.     

Etoposide microcrystals suspended in oil: a new dosage form to peritoneal carcinomatosis in mice.

Etoposide microcrystals suspended in oil (ETOP-OIL) were examined for their therapeutic effects on peritoneal carcinomatosis in mice. Two days after intraperitoneal inoculation with 10(5) P388 leukemia cells/mouse to CDF1 male mice, etoposide at 10-80 mg/kg was administered intraperitoneally in bolus in the form of ETOP-OIL or in the aqueous solution form. In every dose, the survival curve of the mice given ETOP-OIL was statistically significantly improved in spite of its small lethal toxicity, as compared with those given the identical dose of etoposide aqueous solution.     

Radiosensitization by intratumoral administration of cisplatin in a sustained-release drug delivery system.

PURPOSE: Effects of combining local irradiation and intratumoral (i.t.) administration of cisplatin (CDDP) in a sustained-release drug delivery system (epi gel) were studied in a murine SCCVII squamous cell carcinoma model in mice. MATERIALS AND METHODS: The epinephrine injectable gel was used as a drug delivery system. Intratumoral pharmacokinetics of CDDP was studied by using 195mPt-CDDP. The tumor volume quadrupling time (TVQT) and tumor growth delay (TGD) time were used to evaluate the antitumor efficacy of treatment regimens. RESULTS: The concentration and residence of 195mPt-CDDP was significantly higher in tumors treated with 195mpt-CDDP/epi gel than in tumors treated with 195mPt CDDP gel or 195mPt-CDDP suspension. Intratumoral administration of CDDP/epi gel (4 mg/kg) produced an average TGD time of 15.5 +/- 2.8 days, which was 5.2 - 7.4 times longer than CDDP suspension i.t. or i.p. When combined with a single dose of radiation (10 Gy), i.t. administration of CDDP/epi gel was 2.0 - 3.6-fold as effective as administered i.t. in suspension (39.2 +/- 4.1 vs. 19.8 +/- 3.9 days of TGD, P < 0.05) or i.p. in solution (39.2 +/- 4.1 vs. 11.0 +/- 1.6 days, P < 0.001) in inhibiting tumor growth and produced 20-60% complete remission of tumors. When combined with fractionated irradiation, pre-irradiation CDDP administration was more effective than post-radiation administration (26.7 vs. 12.1 days of TGD, P < 0.05). Mice treated with CDDP/epi gel i.t. alone or in combination with irradiation, had little systemic toxicity. CONCLUSIONS: Intratumoral administration of CDDP using the sustained-release drug delivery system is an efficient and safe method to maximize the drug concentration in tumor, minimize the systemic toxicity and enhance antitumor efficacy of irradiation.