Plasma of a patient with metastatic colon carcinoma was perfused over Formalin and heat-killed S. aureus, in an extracorporeal filtration apparatus, in order to nonspecifically remove IgG and its complexes. Twenty ex vivo absorption procedures were done, over a five-month period, with a minimum of discomfort to the patient. Extracorporeal perfusion of plasma on S. aureus effectively reduced the levels of IgG and immune complexes in the perfused plasma. The nonspecific removal of IgG resulted in 1) slight biochemical alterations in the serum, 2) a transient reduction in the serum blocking activity and appearance of complement-dependent serum cytotoxicity, 3) an increase in the serum IgM levels, 4) a transient increase in the Ig surface-bearing lymphocytes and a decrease in "E" rosetting lymphocytes in the first 24-48 hours postperfusion, particularly during the early treatments, 5) an improvement in general condition of the patient and decrease in tumor size, and 6) histological changes in the tumor consistent with tumor destruction. The potential problems and clinical applications of procedures involving ex vivo specific or nonspecific immunoabsorbents are discussed.
Inbred WF rats were inoculated with crude suspensions prepared from liver and gut tissue of 12- to 15-day fetuses of the same strain. Rats previously unsensitized to syngeneic embryonic tissue were inoculated with fetal material sc three times during exposure to 1, 2-dimethylhydrazine dihydrochloride (DMH), a gastrointestinal (GI) carcinogen in rodents. Properly timed immunization inhibited the development, growth, and metastasis of primary GI tumors. This effects was observed in both sexes; however, it was more prounced in male rats. Nine WF rats with DMH-induced carcinoma of the GI tract were inoculated sc with syngeneic fetal tissue. Of 9 rats, 7 rejected the embryonal tissue implants, which thus demonstrated the presence of a concomitant immune response to embryonic antigen(s). Two rats in which fetal tissue grew out to palpable nodules had multiple GI tumors with metastasis and extra-GI tumors, i.e., a massive tumor load. Ten other rats with DMH-induced GI tumors were treated with unblocking serum. The unblocking serum was inoculated to counteract serum-blocking factors in vivo. These rats were inoculated intradermally with syngeneic fetal tissue. In all 10 rats, inflammation and necrosis were noted at the inoculation site after 24-72 hours, which thus demonstrated a delayed hypersensitivity reaction to embryonic antigens. Our experiments suggest that embryonic antigens common to fetal and tumor cells can induce immunity in an autochthonous host and can act as rejection antigens.
A 1,2-dimethylhydrazine dihydrochloride-induced rat gastrointestinal tract tumor model was used to study the phenomenon of immunologic surveillance. In two different sets of experiments, a properly timed administration of antithymocyte globulin resulted in earlier tumor appearance, increased numbers of tumors, and increased multiplicity of gastrointestinal tumors. Results obtained from histologic examination of the gastrointestinal tract at different times after the last dose of 1,2-dimethylhydrazine dihydrochloride suggested that a normally functioning immune system effectively suppressed the growth of some nascent tumors. However, the immunosuppression of the host with antithymocyte globulin allowed the development of foci of microtumors into grossly visible neoplasms. Our experiments supported the concept that immunologic surveillance against neoplasia depends on the thymus cell system, although other possible mechanisms were not excluded.
The effect of multimodal immunotherapy was studied in WF rats bearing primary gastrointestinal (GI) tumors induced by 1,2-dimethylhydrazine dihydrochloride. The alterations induced in antitumor immune responses of the treated rats were studied in vitro and were correlated with tumor status in vivo. Multimodal immunotherapy consisted of unblocking serum, unblocked lymphoid cells, and levamisole. Such immunologic intervention resulted in significant inhibition of tumor growth, inhibition of metastases, and prolonged survival of the host. Serum blocking activity could be completely counteracted in 6 rats, all of which showed complete tumor regression. Of 20 rats, 8 showed inadequate counteraction of serum blocking activity and transient appearance of cytotoxic antibodies. All 8 rats showed marked tumor inhibition and prolonged survival. Six remaining rats succumbed from either GI or extra-GI tumors, although they survived significantly longer than untreated rats; these 6 rats had only transient counteraction of their serum blocking activity. All 20 tumors in 14 rats of the therapy group showed histologic evidence of tumor rejection. Our studies suggested that a complete counteraction of blocking activity in conjunction with methods capable of improving the specific and nonspecific immune competence of the host may be important to achieve optimal antitumor effects.
Accumulating evidence shows that miRNAs play a role in drug resistance. Despite these observations, little is known about the identities of the miRNAs involved in drug resistance and their downstream targets. In the present study, we identified miR-296-5p for which a tumor suppressive role has been previously described, as a miRNA that is involved in paclitaxel drug resistance in triple negative breast cancer (TNBC) cells. Enforced expression of miR-296-5p suppressed cell growth, migration, and invasion in MDA-MB-231 breast cancer cells. Using a microarray approach, we identified BCL2-related Ovarian Killer (BOK), a pro-apoptotic gene as a target of miR-296-5p. BOK levels were validated BOK levels in miR-296-5p transfected MDA-MB-231 and MDA-MB-468 cells using real-time PCR and Western blot. Our results demonstrated that over-expression of miR-296-5p down-regulated BOK expression in TNBC cells. Transfection of miR-296-5p significantly suppressed luciferase reporters containing wild-type BOK-3'-UTR constructs. In contrast, mutant BOK-3'-UTR constructs were unaffected by ectopic miR-296-5p. Furthermore, BOK expression was induced in the presence of paclitaxel, but ectopic miR-296-5p significantly suppressed BOK induction by paclitaxel treatment compared to the control cells. These data provide new insights on the role of miRNAs in drug resistance and suggests that therapeutic strategies against miR-296-5p may be warranted. Citation Format: Onyeagucha BC, Rajamanickam S, Subbarayalu P, Bansal B, Bansal H, Chang Y-F, Timilsina S, Abdelfaltah N, Eedunuri VK, Rao MK. Down-regulation of Bcl2-related ovarian killer (BOK) by miR-296-5p protects breast cancer cells from paclitaxel-induced apoptosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-03-04.
The effect of multimodal immunotherapy was studied in rats bearing primary gastrointestinal tumors induced by 1,2-dimethylhydrazine dihydrochloride. Multimodal immune manipulation consisted of combinations of splenectomy, C. parvum, unblocking serum, unblocked lymphoid cells, and levamisole. Such immunologic intervention resulted in significant inhibition of tumor growth, and their metastasis. Ten of 10 untreated rats, 8 of 8 rats treated with splenectomy alone and 10 of 10 rats treated with normal rabbit serum died of progressive tumor growth. None of the rats treated with combinations of splenectomy, unblocking serum, unblocked lymphoid cells, C. parvum and levamisole succumbed to progressive tumor growth during the observation period. The histologic evidence of tumor destruction was obtained in 18 of 22 tumors in rats of groups receiving multimodal immunotherapy.
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