Immunological Approaches In Rat Brain Tumor Models

The tolerance of the central nervous system (CNS) for activated host immune reactions indicates that the effects of immunotherapy might be decreased for brain tumors. Iwadate et al., [35] developed an interleukin-2 producing 9L rat gliosarcoma and assessed the effect of secretion of interleukin-2 on the growth and immunological responses to the tumor implanted subcutaneously and intracranially. The Fischer 344 rats rejected the 9L/IL-2 tumors when implanted subcutaneously; however, the same tumors cells implanted intracranially grew tumors albeit with a slower growth rate than with the parental 9L cells. Lefranc et al., [36] carried out similar studies with 9L gliosarcoma cells transfected to produce GM-CSF and demonstrated that implantation of these cells prevented tumor growth. Local delivery of carmus-tine (BCNU) from biodegradable polymers prolongs survival in rats bearing intracranial 9L gliosarcoma [37]. Interleukin-2 can also produce a potent antitumor immune response and improve the survival of animals bearing brain tumors. Several methods have been developed and studied for encapsulation of interleukin-2 into polymeric vehicles that can be implanted into brain tumor models [38]. Fischer 344 rats bearing intracranial 9L gliosarcoma received an intracranial implant of empty microspheres or micro-spheres containing interleukin-2. The combination treatment of microspheres containing interleukin-2 along with 10 per cent BCNU polymer resulted in a median survival of 45.5 days while treatment with the interleukin-2-containing microspheres alone or the 10 per cent BCNU polymer alone resulted in median survival times of 24 and 32.5 days, respectively. The untreated controls survived a median of 18 days [37].

Transforming growth factor-beta is well known to be an immunosupressive cytokine and inactivating it may prolong survival of tumor-bearing animals. The cDNA for simian TGF-beta 2 was ligated in antisense orientation into the episomal plasmid mammalian vector pCEP-4 and transfected into rat C6 glioma cells [39]. Adult female Wistar rats bearing intracranial C6 glioma were injected subcu-taneously with saline, C6 glioma cells or TGF-beta-antisense-modified C6 glioma cells. The survival of tumor-bearing rats injected with the TGF-beta-antisense-modified C6 glioma cells was significantly longer than that of animals injected with saline or with parental C6 glioma cells.

Malignant astrocytic tumors are characterized by aggressive, diffuse migration of tumor astrocytes into the brain parenchyma. Gastrin is a brain neuro-peptide that is able to significantly modulate astro-cytic tumor migration controlling both invasion and motility [40-42]. Gastrin belongs to the cholecysto-kinin (CCK) peptide family and is widely distributed in the brain. The rat C6 glioma expresses the CCKB receptor while the 9L gliosarcoma expresses the CCKA and CCKC receptors. When animals bearing intracranial C6 glioma and the 9L gliosarcoma tumors were treated with gastrin, animals with the C6 glioma but not animals with the 9L gliosarcoma showed a survival benefit.

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