Phosphoramidon, a novel matrix metalloproteinase inhibitor, inhibits significantly tumor growth independently of the application route (intraperitoneal [i.p.] versus intravenous [i.v.]) in a rat model of peritoneal carcinomatosis

Introduction: Occurrence of peritoneal carcinomatosis remains still an unsolved problem in gastrointestinal cancer. Over the last years, novel antineoplastic substances such as matrix metalloproteinase (MMP) inhibitors have been investigated in animal models to achieve a decrease of tumor growth. The aim of the study was to determine whether i) Phosphoramidon, an MMP inhibitor, can prevent or diminish i.p. tumor growth, and ii) whether direct i.p. administration of Phosphoramidon is superior to the i.v. route.

Methods: In WAG rats (weight, 250–300g) devided in 2 groups, peritoneal carcinomatosis was induced by tumor cell transfer (5×1,000,000 cells of an adenocarcinoma cell line CC–531; Cell-Lines Service, Heidelberg, Germany). Phosphoramidon (0.46 microM; 7ml; Morphochem AG, Munich, Germany) was given either i) directly (i.p. administration) immediately after tumor cell transfer or ii) fractionated (i.v.) on days(d) 3, 6, 9, 12, 15 postoperatively. Twenty five d after tumor cell transfer, tumor growth was quantified by tumor weight of the greater omentum and the mesenteric site, number and size of detectable tumor lesions, occurrence of hepatic and pulmonary metastases and the amount of ascites.

Results: Table 1. Tumor weight [g] and size [qcm] as representative parameters for quantification of tumor growth comparing the effect of Phosphoramidon given i.p. or i.v. after tumor cell transfer vs. no treatment (not shown) (*, P<0.05; t test–SPSS for Windows).

Summary: 1) Phosphoramidon was highly effective to diminish i.p. tumor growth after direct intraoperative i.p. application. 2) The effect of i.p. administration using this potential drug was more pronounced than i.v. treatment.

Conclusion: The results suggest that the MMP inhibitor Phosphoramidon appears to be a promising antineoplastic substance to overcome dysadvantageous tumor growth at the peritoneal site. Additional studies should be focussed on possible alterations of healing of anastomoses and wounds by this agent.

n=8 rats per group	Tumor weight [g]		Size of tumor lesions [cm 2 ]
i.p.	i.v.	i.p.	i.v.
Greater omentum	1.60±1.01 *	2.40±0.86 *	1.38±1.06 *	2.12±0.83 *
Mesenteric site	2.55±0.48 *	3.66±0.73 *	2.50±0.76 *	4.00±0.76 *

Keywords: Experimental peritoneal carcinomatosis, chemotherapy, phosphoramidon, rat model