Experimental study on intraperitoneal and intravenous administration of anti-tumor agents for liver metastasis

Intraperitoneal chemotherapy has been the treatment for peritoneal seedings. Most of the anti-tumor agent administered intraperitoneally is absorbed from visceral peritoneum, gets into the portal vein system and reaches the liver. Theoretically, intraperitoneal administration of anti-tumor agents must show equivalent effects on the liver metastasis to portal vein infusion. We compared the efficacy of intraperitoneal and intravenous administration of 5-FU, CDDP and CPT-11, using colon 26 mouse liver metastasis model. Intraperitoneal administration of 5-FU or CPT-11 was statistically superior to intravenous administration to diminish the liver metastatic deposits. CDDP experiment did not show a statistical difference, but the superiority intraperitoneal administration was recognized. Intraperitoneal administration of anti-tumor agents is more effective for not only peritoneal seedings but also liver metastases than intravenous administration. Intraperitoneal chemotherapy might be an effective adjuvant chemotherapy for gastrointestinal malignancies.     

Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

CPT-11 is an effective antitumor agent for gastrointestinal malignancy, but the optimum route of administration is unclear. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. CPT-11 (40 mg/kg) was injected intraperitoneally or intravenously on days 2 and 5 after inoculation of tumor cells. Intraperitoneal administration of CPT-11 was significantly more effective than intravenous administration for control of both peritoneal seeding and liver metastasis. Intraperitoneal administration of CPT-11 may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

Rationale for the administration of systemic 5-FU in combination with heated intraperitonal oxaliplatin

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is the standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal absorption of HIPEC OX.

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous Vasopressin in non-resectable pancreas cancer

Background: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity.Aim: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer.Patients/methods: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750–1500 mg/m² and intravenous Leucovorin 100 mg/m² for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed.Results: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8–54.1+), and median survival was 8.0 months (0.8–54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4 ± 2.5 and 6.1 ± 5.4 mol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment.Conclusion: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.     

Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

Paclitaxel is an effective antitumor agent that shows ideal pharmacological characteristics for intraperitoneal chemotherapy. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of Colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. Paclitaxel (20 mg/kg) was injected into the peritoneal seeding model intraperitoneally or intravenously on day 2 and 4 after inoculation of tumor cells. Paclitaxel (30 mg/kg) was injected into the liver metastasis model intraperitoneally and intravenously on days 4 and 8 after inoculation of tumor cells. Median survival time for intraperitoneal administration (17.50 +/- 0.86 days) was longer than that for intravenous administration (13.70 +/- 0.47 days) in the peritoneal seeding model experiment. Median survival time for intraperitoneal administration (19.78 +/- 0.74 days) was longer than that for intravenous administration (17.50 +/- 0.54 days) in the liver metastasis model experiment. Intraperitoneal administration of paclitaxel may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

CD133<Superscript>+</Superscript> niches and single cells in glioblastoma have different phenotypes

Putative CD133⁺ brain tumor stem cells have been shown to be located in niches and as single cells. This is the first study providing insight into the different phenotypes of CD133⁺ cells in glioblastoma according to localization. Paraffin sections were stained by double immunofluorescence with CD133 and the candidate stem cell markers Sox2, Bmi-1, EGFR, podoplanin and nestin, the proliferation marker Ki67 and the endothelial cell markers CD31, CD34, and VWF. Cell counting showed that the CD133⁺ cells in the niches had a significantly higher expression of Sox2, EGFR and nestin compared to CD133⁺ single cells, but only a 3% Ki67 labeling index versus 14% found for CD133⁺ single cells. Only low endothelial cell marker expression was found in the niches or the CD133⁻ tumor areas, while 43% CD133⁺/CD31⁺ and 25% CD133⁺/CD34⁺ single cells were found. CD133⁺ blood vessels within CD133⁺ niches were less proliferative and more often Bmi-1⁺ than CD133⁺ blood vessels outside niches. In conclusion, different CD133⁺ cell phenotypes exist according to the in situ localization, and also the phenotype of CD133⁺ blood vessels vary according to the localization. CD133⁺ niches contain stem-like cells with a lower proliferation index than CD133⁺ single cells, which have an endothelial differentiation profile suggesting a role in angiogenesis.     

Digitonin enhances the efficacy of carboplatin in liver tumour after intra-arterial administration

 Platinum-containing drugs enter the cell slowly and have a poor tissue penetration. Increasing the permeability of the cell membrane might increase the intracellular drug concentration. Digitonin, a detergent that increases cell permeability by binding to cholesterol molecules in the cell membrane, can increase cisplatin accumulation and reduce tumour growth in vitro. The aim of this study was to determine whether digitonin could increase the efficacy of carboplatin (CBDCA) in vivo. In LH rats, a hepatoma was implanted in the liver. At 7 days after implantation, digitonin (or saline in the control group) was infused via the hepatic artery and, 10 min later, CBDCA was injected. Biopsies from the tumour and liver parenchyma were obtained after 1 h. The concentration of platinum measured in the liver tumours was higher in the digitonin group than in the control groups. In the liver parenchyma the concentrations were of the same magnitude. Measured with the ¹³³Xe-clearance technique, digitonin did not alter the tumour blood flow. Digitonin enhanced the tumour-growth-retarding effect of CBDCA given intra-aterially at 5 mg/kg but not at 25 mg/kg. No increase in toxicity was observed for digitonin given together with CBDCA at 5 mg/kg. Systemic administration of CBDCA was not influenced by digitonin. These findings demonstrate that pretreatment with digitonin increases the tumour uptake of CBDCA and potentiates the cytotoxic effect of CBDCA. Received: 21 September 1996 / Accepted: 17 March 1997     

Gastric mucosal blood flow and gastric secretion following intravenous administration of 5-fluorouracil in anesthetized rats

 Acute gastric mucosal lesions are often observed after the intravenous administration of high doses of anticancer drugs. To investigate the acute toxic effects of such anticancer therapy on the gastric mucosa, 5-fluorouracil (5-FU) was administered intravenously to anesthetized rats. Gastric mucosal blood flow (GMBF) was measured continuously using laser Doppler velocimetry. Acid secretion was measured using a perfusion method for 1h after the administration of 5-FU. No significant change was observed with a low dose of 5-FU (50 mg/kg), but a high doses of 5-FU (100 or 200 mg/kg) caused a significant decrease in GMBF in a dose-dependent manner. The selective antagonist of the muscarinic acetylcholine receptor, pirenzepine, prevented the decrease in GMBF with high doses of 5-FU. Acid secretion decreased after the administration of 5-FU, but not significantly. This study indicates that a decrease in GMBF may be an important factor in gastric mucosal injury induced by chemotherapy. Pirenzepine may prevent the gastric mucosal lesions which are induced by the administration of 5-FU. Received: 7 December 1995/Accepted: 29 June 1996     

Human melanoma growth in the peritoneal cavity of the athymic mouse—A model for in vivo study of cell-mediated immunity

Intraperitoneal injections of 2 × 10⁷ SH-Me cells (human metastatic melanoma cells) to 20 Balb/c nu/nu mice (Group A) and 1 × 10⁷ cells to 20 mice (Group B) were performed. All animals were studied clinicopathologically. Five animals in Group A were sacrificed serially, revealing marked tumor growth of the melanoma within the peritoneal cavity. These tumors grew in multiple nodular configurations and tumor ascites was present by the third week. The remaining 15 animals in Group A were allowed to progress and seven subsequently died with mouse viral hepatitis (MVH). These animals had suppressed tumor growth. The remaining eight animals died of peritoneal carcinomatosis with survival time of 24.1 ± 5.0 days. Eight of the animals in Group B died of mouse viral hepatitis while the remainder died of peritoneal tumor without distant metastasis. Survival time in these animals was 23.8 ± 2.6 days. Both 2 × 10⁷ and 1 × 10⁷ tumor cells injected intraperitoneally will constantly produce tumor nodules in non-MHV-infected nude mice with similar survival. This experimental model has proven useful for in vivo study to assess the immunoreactivity of melanoma patient cells reactive against target tumor cells.     

Intraperitoneal and intrapleural gemcitabine in patients with advanced pancreatic cancer

We performed intraperitoneal and intrapleural dosing gemcitabine (GEM) to eight patients with advanced pancreatic cancer having peritoneal or pleural carcinomatosis and evaluated its actions and safety. GEM (500 mg/m2) was infused into the abdominal cavity or thoracic cavity after drainage of peritoneal or pleural effusion. We checked the change of serum GEM concentration and the side effects after the GEM administration. Then, we repeated the GEM administration observing their systematic symptoms and evaluated the alteration of peritoneal or pleural effusion and cytology. Plasma concentration of GEM by infusing into the abdominal cavity or thoracic cavity was lower than by intravenous injection. In three of the five cases of peritoneal carcinomatosis, intraperitoneal administration revealed a decrease of peritoneal effusion. In two of the three cases of pleural carcinomatosis, intrapleural administration revealed a decrease of pleural effusion. Four cases had leukocytopenia of grade 1/2, three cases had thrombocytopenia, and two cases had alopecia as side effects, although all of them were minor side effects. Intraperitoneal and intrapleural dosing GEM had minor side effects and could improve QOL for the patients with advanced pancreatic cancer associated with peritoneal or pleural carcinomatosis.     

Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies

BACKGROUND AND OBJECTIVES: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue absorption of intraperitoneal versus intravenous oxaliplatin. METHODS: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups according to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraperitoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplatin (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At the end of each procedure the animals were sacrificed. Selected tissue samples were taken in the second phase only. For all samples, platinum levels were measured by direct current (d-c) plasma emission spectroscopy. RESULTS: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 (+/- 5):1 for intraperitoneal delivery as opposed to 1:5 (+/- 2) for intravenous delivery (P = 0.0059). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 (+/- 8):1. With the exception of the kidneys and the mesenteric nodes, tissue samples in the hyperthermic group exhibited increased oxaliplatin concentrations. These differences were not significant. For both groups colon tissues had the highest oxaliplatin concentrations. CONCLUSIONS: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal administration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxaliplatin for microscopic residual tumor after surgical resection of colon malignancies.     

Cisplatin combined with prostaglandin E1 chemotherapy in rat peritoneal carcinomatosis

Cisplatin intraperitoneal (i.p.) chemotherapy is frequently performed for patients with peritoneal carcinomatosis. However, cisplatin penetrates only the surface of the peritoneal tumor and has serious side effects on renal cells. Thus, cisplatin i.p. chemotherapy had been limited to use for these patients. Prostaglandin E1 (PGE1) has been used for reducing the toxic effects of anticancer drugs because of its cytoprotective effects and has been reported to enhance tumoricidal activity of anticancer drugs. In our study, the effects of PGE1 on the rat peritoneal carcinomatosis model treated with cisplatin i.p. chemotherapy were evaluated. Cisplatin (5 mg/kg) was given in an i.p. administration to 70 tumor-free rats. PGE1 was administered to 35 rats through the tail vein at an infusion rate of 0.1 microg/kg/min (1 ml/hr), and the remaining 35 rats were injected with physiological saline. Forty rats were given an i.p. injection of 1 x 10(7) AH100B cells. Ten days after injection, cisplatin (5 mg/kg) was administered with PGE1 to 20 and the remaining 20 were injected with physiological saline. The accumulation of platinum in the tissues and apoptotic renal cells were analyzed. The maximum concentrations of platinum in the kidneys of PGE1 untreated rats (tumor-free: 10.11 microg/g; tumor-bearing: 11.45 microg/g) did not differ from those of platinum in the kidneys of PGE1-treated rats (tumor-free: 10.28 microg/g; tumor-bearing: 13.28 microg/g). The number of apoptotic renal cells was significantly reduced by PGE1 administration in both tumor-free and tumor-bearing rats. Moreover, PGE1 increased the maximum platinum concentration in tumor masses (5.31 microg/g) of the treated group compared with that in tumor mass of the control group (2.72 microg/g, p = 0.009). These results indicate that PGE1 may increase the anticancer effect of cisplatin by increasing tumor platinum concentration and may reduce the chance of cisplatin-induced renal failure. Intraperitoneal cisplatin chemotherapy combined with PGE1 treatment may have a therapeutic benefit for patients with peritoneal carcinomatosis.     

Experimental study to evaluate the usefulness of S-1 in a model of peritoneal dissemination of gastric cancer

Background

Favorable results have been reported for the novel oral anticancer agent S-1 (TS-1^®) in clinical studies of advanced gastric cancer with peritoneal dissemination. In the present study we assessed its pharmacokinetics, inhibitory effects, and effect on survival time in an animal model.

Methods

A model of peritoneal dissemination was created by intraperitoneally implanting 4-week-old female BALBc nu/nu mice with the human gastric cancer cell line MKN-45 after transfection with a fluorescent protein-expressing vector. Pharmacokinetics were investigated by measuring intratumor, peritoneal lining, and blood concentrations after the administration of S-1 and fluorouracil (5-FU). The effect of S-1 on survival time was also assessed, by administration once daily to seven animals per group, starting on day 7 after implantation, and survival time was compared with that of an untreated control group. The inhibitory effect of S-1 on peritoneal dissemination was evaluated by killing mice at the start of administration, and 1 and 3 weeks after the start of administration, and examining them for the presence of peritoneal dissemination under a fluorescence stereomicroscope.

Results

Maintenance of high 5-FU concentrations in the intraperitoneal tumors was confirmed in the S-1 group, and survival time was prolonged without any decrease in oral food intake or body weight.

Conclusion

Assessment in a model of peritoneal dissemination of gastric cancer showed that the novel oral anticancer agent S-1 was effective against peritoneal dissemination, and that it improved the survival rate.

     

Safety and efficacy of intraperitoneal injection of etoposide in oil suspension in mice with peritoneal carcinomatosis

We compared the safety and efficacy in mice with peritoneal carcinomatosis of two etoposide formulations: an aqueous solution (Etp-sol) and particles suspended in oil (the addition products of iodine and the ethyl esters of the fatty acids obtained from poppy-seed oil (Lipiodol) or sesame oil; Etp-oil). We also investigated tissue distribution of etoposide in rats treated with Etp-oil and Etp-sol. Etoposide was injected intraperitoneally at concentrations ranging from 52 to 392 mg/kg (increasing geometrically by a factor of 1.4). The 50% lethal dose (LD₅₀), determined over a 2-week period of observation, was 135 mg/kg for Etp-oil and 108 mg/kg for Etp-sol. Autopsy findings included macroscopic intestinal bleeding, necrosis of the intestinal mucosa, and pulmonary congestion in mice from both treatment groups. In the efficacy trials. 10⁶ P388 leukemia cells were transplanted into CDF₁ male mice, and Etp-oil and Etp-sol were injected at doses of 20 mg/kg and 80 mg/kg. In the groups receiving the 20 mg/kg dose, 11 of 19 mice in the Etp-oil group survived to day 60 compared with 3 of 20 mice in the Etp-sol group. Toxicity-related deaths occurred in 1 of 20 mice treated with 80 mg/kg Etp-oil and in 8 of 20 mice treated with 80 mg/kg Etp-sol. No cancer-related deaths were associated with the 80 mg/kg dose in either treatment group. Our findings showed that the Etp-oil was associated with a lower toxicity and a higher efficacy than the Etp-sol. To evaluate tissue distribution, rats were injected intraperitoneally with 5 mg/kg body weight of Etp-sol or Etp-oil. The tissue distribution of etoposide was subsequently analyzed by high performance liquid chromatography. Compared with Etp-sol, Etp-oil delivered significantly greater amounts of etoposide and for a longer period to the omentum, taken as representative of the intraperitoneal tissue, and the etoposide concentration in blood plasma was increased more slowly and decreased more gradually.     

腺病毒介导p53基因联合胸腺肽治疗腹腔转移癌的实验研究

 目的 评价p53腺病毒注射液与胸腺肽α1（Tα1）联合腹腔给药对腹膜转移癌模型的协同抑制作用。方法 建立H22腹水瘤的昆明小鼠模型，48 h后以p53腺病毒注射液、Tα1等腹腔注射，治疗周期为1周，治疗后测量腹围、体重，计量腹水，计数瘤细胞数，以流式细胞分析检测瘤细胞凋亡、死亡比例及细胞周期。结果 p53腺病毒注射液腹腔局部给药1周，出现瘤细胞G0／G1期阻滞；其和Tα1联用后，未生成腹水的小鼠增多，生成腹水的小鼠的腹水量和瘤细胞数均较单用时明显减少，死亡细胞数明显增高。结论 p53腺病毒注射液可阻滞腹水瘤细胞增生，联合Tα1腹腔给药，对瘤细胞具有协同杀伤作用，抑制腹膜转移癌的发生。     

Pharmacology of intraperitoneal CPT-11

CPT-11 is clearly one of the most important new anticancer drugs developed in the last few decades, and CPT-11 combined with 5-fluorouracil (5-FU) and leucovorin is considered as reference first-line chemotherapy in the treatment of metastatic colorectal cancer. CPT-11 has a complex pharmacologic profile in vivo, and it needs caboxylesterase-mediated biotransformation to SN-38 before production of its cytotoxic effect. Intraperitoneal administration of CPT-11 has been studied recently in murine models and presented some potential advantage over the intravenous (i.v.) route. Intraperitoneal administration of CPT-11 may be more effective than i.v. administration not only for peritoneal seeding but also for liver metastases. Also, these effects may occur with less toxicity by intraperitoneal administration. Intraperitoneal chemotherapy containing CPT-11 might be an essential option for prevention and treatment of cancerous dissemination of gastrointestinal malignancy.     

Pharmacokinetics of fluorouracil by intravenous or intraarterial injection

High-performance liquid chromatographic (HPLC) analysis of fluorouracil (5-FU) content of the blood and colon of rabbits is described. There was no marked difference in the plasma 5-FU level and blood concentration time curve following intravenous (I.V.) (ear vein) or intraarterial (I.A.) (inferior mesenteric artery) injection of 5-FU 15 mg/kg. However, the distribution of 5-FU in the colon after I.A. administration was quite different that after I.V. administration. At 10, 20 and 30 minutes, the 5-FU content in the colon was shown to be 31-, 17- and 14-fold higher with I.A. than with I.V.. Colonic tissue AUC_0–480 min. was 2453 and 690 min/mg/ml respectively (p<0.05). It is suggested that to inject 5-FU into selected arteries to treat advanced colorectal cancer may be more useful than I.V. administration.     

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.     

Effect of intraperitoneal chemotherapy and fibrinolytic therapy on tumor implantation in wound sites

Failure of surgical treatment for gastrointestinal cancers is often caused by recurrence of the tumor in traumatized peritoneal surfaces. This study examined the effect of intraperitoneal administration of doxorubicin and recombinant tissue plasminogen activator (rt-PA), a fibrinolytic agent, on incidence and volume of postoperative tumor implants in peritoneal wounds. Prior to randomization, a surgical wound was created on the right parietal peritoneum of 110 BDIX rats and 6 × 10⁵ DHD/K12 colon cancer cells were inoculated intraperitoneally (ip). The control group was given an intraperitoneal injection of saline. Five groups received 1 mg/kg of ip doxorubicin at different times postoperatively: at the end of surgery (DO), 3 hr after surgery (D + 3), postoperative day 1 (Dl), postoperative day 3 (D3), and postoperative day 7(D7). In a second set of experiments, five groups of rats received, in addition to postoperative doxorubicin, 5 mg/kg of intraoperative ip rt-PA. Incidence and volume of tumor implants in peritoneal wounds were assessed for each group 20 days after the tumor inoculation. All rats of the control group (incidence = 100%) developed tumor implants in peritoneal wounds. Mean (SD) volume was 16.2 (4.7) mm³. When administered at DO, D + 3, and Dl intraperitoneal doxorubicin reduced significantly the incidence and volume of tumor implants in wounds. Postoperative administration of doxorubicin at D3 and D7 did not affect significantly the incidence and the volume of tumor implants in peritoneal wounds. When rt-PA was administered intraoperatively, ip injection of doxorubicin at any postoperative timing decreased significantly the incidence and volume of tumor implants. In conclusion, ip doxorubicin administered before postoperative D3 may act on tumor cell implanted in peritoneal wounds. Delayed (D3, D7) ip administration of doxorubicin does not prevent the development of tumor implants in peritoneal wounds. Intraoperative administration of rt-PA may significantly increase the efficacy of delayed ip chemotherapy. © 1996 Wiley-Liss, Inc.