Targeted intraabdominal chemotherapy for peritoneal carcinomatosis.
The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B 1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcell; Bavarian Nordic, Martinsried, Germany). Adult Balb/c mice were inoculated intraperitoneally (i.p.) with 1 x 10(6) colon cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1 expressing cells. Peritoneal tumour volume and tumour viability were assessed 10 days after tumour inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day five and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer. In summary, by using GFP-transfected colon 26 tumour cells in mice we established a well reproducible animal model of metastatic peritoneal cancer. Fluorescent imaging of GFP-transfected tumour was used to demonstrate tumour distribution in the peritoneal cavity and to estimate tumour growth and tumour response to treatment in this model. The application of Capcell and ifosfamide into the peritoneal cavity is a safe and well tolerated procedure in animal models and may help to target chemotherapeutic agents specifically at metastatic peritoneal cancer.
Samel
S
S
University of Göttingen, Germany. Stephan.samel@web.de
Löhr
M
M
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D002482:Cellulose / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; D002482:Cellulose; C020254:cellulose sulfate; D003577:Cytochrome P-450 Enzyme System; D007069:Ifosfamide