ABSTRACT

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Purpose: Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response. Experimental Design: Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFNg^transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. Results: Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 Ag/mL CA4P significantly enhanced proliferation and IFNg production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester with CA4P and immunization further retarded tumor growth. Conclusion: Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.

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Development of tissue engineering creates multiple potentials for clinical treatment and scientific research. Biodegradable collagen matrices have been found to support simultaneous autotransplantation of hepatocytes after major liver resection. Dynamic angiogenesis in biodegradable devices (BDD) and nondegradable devices (NDD) transplanted into the renal subcapsule and subcutaneous tissue was measured by the distribution of radiolabeled red blood cells and serum albumin. The circulation, microvascular integrity, and capacities of endothelial cells (adhesion, proliferation, and migration) were investigated within 2 weeks after subcutaneous transplantation of both devices. Patterns of tumor cell growth in both devices were morphologically studied. After subcutaneous transplantation, significant angiogenesis was noted at 1 week in BDD implants and from 2 weeks and on in NDD implants, with an increase in implant blood and plasma volumes. Leakage index of radiolabeled albumin in NDD implants was significantly higher than in BDD implants, while the leakage index 2 weeks after BDD implant was similar to that in subcutaneous tissues. Adhesion, proliferation and migration rates of endothelial cells isolated from both devices were higher than from subcutaneous tissues. Endothelial proliferation and migration rates in BDD implants were significantly higher at 1 week, while in NDD at 2 weeks. Tumor cells migrated and grew on the top surface of NDD with a flattened shape, while growing within the BDD forming a round mass. Endothelial capacities, angiogenetic procedure, and biological and physical characteristics of the device contribute to patterns of tumor cell growth in the device. Biodegradable collagen matrix with three-dimensional structure is suitable for simultaneous transplantation with cells without prevascularization.