Combined Intratumoral Administration Of Cationic Liposome Coating Flt3L Plasmid DNA And Intraperitoneal Cisplatin Chemotherapy To Treat Pre-existing Mice Colon Carcinoma

Purpose: Immuno-cell Targeting represents a new strategy for the development of antitumor biochemical therapies. Flt3 ligand (FL) is a member of a small family of growth factors that stimulate the proliferation of hematopoietic stem cells by binding to and activating distinct tyrosine kinase receptors. Expression of the Flt3 receptor is primarily restricted to the most primitive hematopoietic progenitor cells, and FL stimulates the proliferation in vitro and the expansion and mobilization in vivo of stem and progenitor cells. FL as a single factor has little proliferative activity on these stem and progenitor cells, but it synergizes with a wide range of other colony-stimulating factors and interleukins to stimulate proliferation of thesecells. FL is also an effective agent for mobilizing stem and progenitor cells to peripheral blood. Recent data demonstrating anti-tumor activity of FL suggest that this protein plays a major role in activating the immune system via its ability to stimulate the production of both dendritic and natural killer cells. These Potent Biologic activities of flt3 ligand on HSCs and the development of the immune system have generated much interest and potentially prove quite useful in the clinical application of Flt3 ligand in stem cell transplantation after high dose chemotherapy and in cancer immunotherapy.Materials and Methods: In this experiment, CT26 colon carcinoma model were established in 6-8 weeks BALB/c mice with implanting 106 cell/mouse in the lower right flank and then were injected orthotopically with either cationic liposome coating FU3L plasmid for four times, Cisplatin (2mg/Kg, i.p. once a week for two weeks), or NS. All experiments were performed using individual treatment groups of ten mice for each group. The experimental groups included: group A, untreated controls; group B, DDP treatment alone; group C, intratumoral injections of cationic liposome coating Flt3L plasmid alone; group D, combined DDP and intratumoral injections of cationic liposome coating Flt3L plasmid. On day 7 after implanting, the average diametor of tumor were 0.4~0.6cm, respectively. The mice then received i.p. Injections of DDP (2mg/kg body weight); injections were repeated 1 week later with the same dose. Four injections of cationic liposome coating Flt3L plasmid (each injection was lOOug/mouse in 100 ulof PBS) were given into the tumor on days 7,9,11, and 15. For all animal experiments, the tumor size was measured biweekly using a caliper and expressed as the product of the maximal perpendicular diameters (mm2). Survival was recorded as the percentage of surviving animals on a given day. Then observe the volume of tumor, long-term suvival rate of mice, side effects of chemotherapy and make histological analysis of tumor section as well.Results: Combined Intratumoral Administration of cationic liposome coating Flt3L plasmid DNA in synergy with intraperitoneal Cisplatin Chemotherapy results in significant suppression of tumor growth and prolonged survival.. DDP alone, or Flt3L alone, gave only partial suppression compared with the control (P < 0.05, all observations of DDP + Flt3L compared with other groups). Consistent with the significant suppression of tumor growth in the CTX + DC treated mice, the CTX + DC treated mice had 100% survival. In contrast, there was reduced survival for all of the control groups (P < 0.01, all observations of CTX + DCs compared with other groups). And also observed apparently that tumor cell appears necrosis and karyopycnosis of early stage apoptosis compared with other groups.Conclusion: The present result demonstrated that the stratage of Combined Intratumoral Administration of cationic liposome coating Flt3L plasmid DNA and intraperitoneal Chemotherapy has significant antitumor activitiy In summary, we have established a reproducible and clinically relevant orthotopic treatment model of cancer in immunocompetent mice with application to a variety of therapeutic strategies.