Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine

Kammertoens, Thomas; Gelbmann, Wolfgang; Karle, Peter; Alton, K.; Saller, Robert; Salmons, Brian; Günzburg, Walter H.; Uckert, Wolfgang

doi:10.1038/sj.cgt.7700139

Cited by 24 publications

(22 citation statements)

References 12 publications

(23 reference statements)

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“…24 There was an apparent therapeutic effect that caused a partial or total tumor ablation. This original technique was already applied in patients suffering from pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Combined therapy of experimental pancreatic cancer with CYP2B1 producing cells: Low-dose ifosfamide and local tumor irradiation

et al. 2004

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Local therapy of pancreatic cancer with microencapsulated CYP2B1-producing cells and ifosfamide showed an effect both on the primary tumor and on distant metastatases. This possibly represents a consequence of the activation of immune response. Other studies have demonstrated that local tumor irradiation leads to the activation of the intratumoral lymphocyte infiltration. The aim of our study was to investigate the efficacy of the combined therapy with low-dose irradiation, ifosfamide and CYP2B1-producing cells. Syngenic pancreatic cancer was induced in 38 Lewis-rats by subcutaneous inoculation of 1 ؋ 10 6 (DSL6A) tumor cells. Microencapsulated CYP2B1-producing cells were injected peritumorally 10 --12 weeks after tumor implantation. Animals were randomized to the following groups: 1) control (NaCl, 1 ml i.p.), 2) ifosfamide (50 mg/kg, i.p., (3؋/week), 3) local irradiation with 5 Gy and 4) ifosfamide plus irradiation. The tumor growth was monitored for 3 weeks. The tumor infiltration with CD4؉, CD8؉, NK-cells, microvessel density and proliferation rates were investigated by immunohistochemistry. Cytokine plasma level for TNF-␣ were measured by ELISA. Seven of 9 animals in the group of combined therapy showed an objective response to the therapy. The therapy with ifosfamide or radiation alone showed 5 and 3 responders, respectively. The mean tumor volume was significantly reduced after combined ifosfamide plus radiation therapy in the first week, whereas monotherapy with ifosfamide or radiation significantly decreased tumor growth earliest after 2 and 3 weeks, respectively. The high plasma level of TNF-␣ in the control group was significantly reduced after combined ifosfamide/irradiation treatment. The lymphocyte infiltration and tumor proliferation were not significantly different between the groups. Microvascular density was significantly increased after ifosfamide and ifosfamide plus irradiation therapy. The combination of ifosfamide/CYP2B1-producing cells and irradiation showed an earlier therapeutical effect on the growth of rat pancreatic cancer than the irradiation or ifosfamide alone. There was no evidence of late activation of lymphocyte infiltration and PCNA-positive tumor cells.

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“…24 There was an apparent therapeutic effect that caused a partial or total tumor ablation. This original technique was already applied in patients suffering from pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Combined therapy of experimental pancreatic cancer with CYP2B1 producing cells: Low-dose ifosfamide and local tumor irradiation

et al. 2004

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“…79,82,83 The second category comprises enzymes of human origin, such as cytochrome P450 isophorms. 79,84 Perhaps the two best examples of this strategy are thymidine kinase (TK) and CD, which convert ganciclovir (GCV) and 5-fluorocytosine, respectively, into their toxic drug forms.…”

Section: Mutation Compensationmentioning

confidence: 99%

“…In this regard, results reveal that, for murine mammary tumors, the antitumoral effect mediated by two different suicide gene sytems, CD and cytochrome P450 2B1, is more efficient to each single system alone. 84 This approach is based on the rationale that the permeable toxic metabolites resulting from the CD/5-FC system enhance the overall bystander effect, and therefore a synergistic antitumoral effect can be achieved. 79,94 To date, there are two clinical trials using GDEPT as a treatment for breast cancer.…”

Section: Mutation Compensationmentioning

confidence: 99%

Gene therapy for carcinoma of the breast

2006

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“…18 The therapeutic regimen has also been successfully applied to spontaneously occurring breast carcinoma in dogs. 19 …”

Section: Introductionmentioning

confidence: 99%

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide

et al. 2005

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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 CYP2B1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcellt). Adult Balb/c mice were inoculated intraperitoneally with 1 Â 10 6 colon 26 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 tumor volume and tumor viability were assessed 10 days after tumor 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 5 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.

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Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine

Cited by 24 publications

References 12 publications

Combined therapy of experimental pancreatic cancer with CYP2B1 producing cells: Low-dose ifosfamide and local tumor irradiation

Combined therapy of experimental pancreatic cancer with CYP2B1 producing cells: Low-dose ifosfamide and local tumor irradiation

Gene therapy for carcinoma of the breast

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide

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