We report here the unexpected biological behaviour of the transplantable MC29 virus-induced hepat... more We report here the unexpected biological behaviour of the transplantable MC29 virus-induced hepatoma. This neoplasm, originating from an inbred white Leghorn (Duke) chicken, is maintained in our laboratory by serial in vivo passages in Hunnia hybrid chickens allogeneic to the original host. More than 80% of the tumours developing after subcutaneous inoculation of 3 x 10(6) hepatoma cells into newly hatched chickens grew progressively, while after injection of the same number of cells into 7 days old birds regressive tumour growth was observed. Transplantation from the allogeneic hosts into 7 days old inbred white Leghorn (Duke) chickens also resulted in regression of tumours in the great majority of cases. After inoculation to xenogeneic Japanese quails, progressor tumours developed in both two weeks old and adult birds with a dramatic increase of the frequency of liver metastases. Transplantation to another xenogeneic host, the turkey, revealed an age-related resistance similar to that of Hunnia hybrid chickens.
The effect of syngeneic mouse peritoneal cells (PC) on the growth of four different transplantabl... more The effect of syngeneic mouse peritoneal cells (PC) on the growth of four different transplantable tumours was studied in adoptive transfer experiments (Winn's test). PC from unstimulated mice did not influence the growth of a benzpyrene induced fibrosarcoma (BaF1) and a methylcholantrene induced mastocytoma (P815), but significantly enhanced the growth of a spontaneous adenocarcinoma (Sp4) and Lewis lung carcinoma (LL). PC induced by a single injection of thioglycollate did not influence, whereas PC elicited by proteose peptone markedly enhanced the growth of BaF1 fibrosarcoma. The enhancing effect of peptone induced PC was diminished by a single intraperitoneal dose (100 micrograms/mouse) of polyinosinic-polycytidylic acid (poly I:C) given after peptone injection. Transferring PC obtained after a single injection of poly I:C (100 micrograms intraperitoneally) resulted in retardation of growth of BaF1 fibrosarcoma and Sp4 adenocarcinoma or in a marked decrease in their take depending on the PC/tumour cell ratio. The effector cells involved in the protective effect proved to be different, using these two tumour models. Lewis lung carcinoma and P815 mastocytoma proved to be insensitive to poly I:C-stimulated PC.
Tumours of aged Balb/c mice developed without any conscious experimental interference were excise... more Tumours of aged Balb/c mice developed without any conscious experimental interference were excised and retransplanted to the autochtonous hosts. The autotransplantation resulted in tumour take after a prolonged period of latency or in no take for an extended period of observation (more than 80 days) in 6 out of 19 cases. This can be regarded as a sign of antitumoural resistance, although it seems to be ineffective against development of recidives and metastases or second tumours. The sensitivity of the autotransplantation method in detecting antitumoural resistance was compared to that of the transplantation-excision-retransplantation assay using a benzpyrene induced Balb/c fibrosarcoma; the autotransplantation method proved to be less sensitive. According to these data the existence of some kind of resistance against spontaneous tumour cells cannot be excluded.
Our earlier space experiments demonstrated that the interferon production of human lymphocytes in... more Our earlier space experiments demonstrated that the interferon production of human lymphocytes in microgravity is 4-8 times higher than those of the synchronous ground controls in vitro (Talas et al. 1983). These data suggested that the microgravity has a significant effect on cells. Since the possibilities to perform space-experiments are very limited and our study raised many interesting questions, we wished to simulate microgravity conditions in our laboratory. For this reason we purchased a Rotary Cell Culture System (RCCS) equipment to study different cell lines and human peripheral blood mononuclear cells (PBMCs) in experimental microgravity conditions. RCCS is a horizontally rotated bubble free culture vessel with membrane diffusion gas exchange. We report here an analysis of TNF-alpha (tumor necrosis factor-alpha) production by human PBMCs (control cultures exposed to simulated microgravity in RCCS). The cells were incubated in the presence or absence of either NDV (Newcastle Disease Virus) or one of the different forms (PHA-M or -P) of Phytohaemagglutinin.
Effect of peritoneal cells (PC) from mice treated with a combination of drugs (indomethacin, poly... more Effect of peritoneal cells (PC) from mice treated with a combination of drugs (indomethacin, poly I:C and Syncumar) on the take of Lewis lung (LL) carcinoma was studied in Winn-type adoptive transfer experiments. Transfer of PC from mice given a single intraperitoneal injection of polyinosinic-polycytidylic acid (poly I:C) or indomethacine or Syncumar (100 micrograms of each) per se did not suppress the take of Lewis lung carcinoma in the recipient mice. PC obtained from mice treated with a combination of indomethacin and poly I:C or poly I:C and Syncumar also failed to inhibit the take of the tumour. In contrast, PC collected from mice after a combined treatment with the three drugs (indomethacin + poly I:C + Syncumar) resulted in a 30-60% decrease in tumour take depending on the tumour cell/PC ratio. This effect could not be observed when a single intraperitoneal dose of cyclophosphamide was administered three days before starting of the combined treatment of the donor mice. The effector cells contributing to the tumour inhibitory effect proved to be nonadherent cells, probably large granular lymphocytes (LGL), as their suppressive effect was abrogated after treatment with the lysosomotrop vital dye neutral red.
We studied the properties of activated peritoneal cells (PC) inhibiting the take of SP4 spontaneo... more We studied the properties of activated peritoneal cells (PC) inhibiting the take of SP4 spontaneous adenocarcinoma and Lewis lung carcinoma in syngeneic mice. Treatment of the poly I:C activated PC from Balb/c mice suppressing the take of SP4 tumour with anti-asialo GM1 antibody and complement before transfer did not affect their tumour-inhibitory potential. PC from Balb/c nude mice treated with poly I:C also inhibited the take of SP4 tumour. Spleen cells from untreated or poly I:C treated Balb/c and Balb/c nude mice, however, did not inhibit the take of SP4 adenocarcinoma. Treatment of peritoneal cells activated by a combination of poly I:C, indomethacin and Syncumar (referred to as "combined treatment") with anti-asialo GM1 antibody and complement could not, or could only partly abolish their tumour-inhibitory potential. The cells mediating the suppression of the take of Lewis lung tumour proved to be Thy-1,2+/-, Lyt-1-, Lyt 2.2- cells. We conclude that the activated peritoneal cells inhibiting the take of SP4 adenocarcinoma and Lewis lung tumour are different from NK cells, NC cells and LAK cells and represent a distinct antitumoural effector cell population.
We compared the effects of various potential effector cells of syngeneic or allogeneic origin on ... more We compared the effects of various potential effector cells of syngeneic or allogeneic origin on the take of a spontaneous adenocarcinoma (SP4) and Lewis lung (LL) carcinoma. As reported earlier, syngeneic resident (non-activated) peritoneal cells (PC) did not inhibit the take of these tumours. On the contrary, transfer of resident PC from allogeneic donors suppressed the tumour take. Syngeneic and allogeneic PC activated by poly I:C or by a combination of indomethacin, poly I:C and Syncumar ("combined treatment") inhibited the tumour take to a similar extent. Syngeneic spleen cells (from untreated mice or from donors underwent "combined treatment") did not inhibit the take of Lewis lung tumour. Transfer of activated allogeneic spleen cells resulted in a stronger inhibition of tumour take than the transfer of resident allogeneic spleen cells.
We have found that genomes of human T cell leukemia-lymphoma virus type I (HTLV-I), BK virus (BKV... more We have found that genomes of human T cell leukemia-lymphoma virus type I (HTLV-I), BK virus (BKV), and a hepatitis B virus (HBV) DNA sequence integrated into DNA of a hepatoma-derived cell line contain binding sites for nuclear factor 1 (NF-1), a cellular protein which binds to adenoviral and putative cellular origins of DNA replication. We suggest that cellular origins of DNA replication acquired by oncoviruses may play a role in malignant transformation after reintegration into the cellular genome by providing new targets for cellular factors initiating DNA replication and by perturbing the temporal order of replication.
Presence of human herpes virus type 8 (HHV8), detected by nested PCR, and expression of Epstein-B... more Presence of human herpes virus type 8 (HHV8), detected by nested PCR, and expression of Epstein-Barr virus (EBV), as assessed by immunochemistry and in situ hybridization, were evaluated in 20 primary non-Hodgkin immunoblastic lymphomas (NHL) of the central nervous system (CNS) from patients who died from AIDS, and in 10 samples of cerebral tissues from patients who died from AIDS, without cerebral lymphoma or Kaposi's sarcoma, as controls. Six lymphomas (30%) contained HHV8 sequences, and 19 (95%) expressed EBV; detection of HHV8 was more frequent in patients with Kaposi's sarcoma, than in other subjects (4/6 versus 2/14). Three (30%) controls contained HHV8 sequences, whereas none expressed EBV. AIDS-related CNS NHL is therefore clearly associated with EBV expression, while the presence of HHV8 appears occasional, probably associated with a low tissue viral load. The high frequency of HHV8 in AIDS-related primary CNS NHL patients with Kaposi's sarcoma suggests that this virus could play a role in the pathogenesis of some cerebral lymphomas.
Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating e... more Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating early, in situ neoplasms. Therefore we studied the effect of inhibitors of macrophage and/or NK cell function on the take of transplantable spontaneous murine tumors in syngeneic mice. The treatment of animals with trypan blue, a selective inhibitor of macrophage function, decreased considerably the period of latency of BSP3 adenocarcinoma; however, it did not increase the take of SP4, SP82 and SP84 adenocarcinomas. The treatment of recipients with neutral red, a selective inhibitor of NK cell function, enhanced the take of SP4 adenocarcinoma. The treatment of mice with agents depressing both macrophage and NK cell function (silica or carrageenan) decreased the both macrophage and NK cell function (silica or carrageenan) decreased the period of latency and/or increased the take of SP4, SP82 and SP84 adenocarcinomas. Carrageenan or a combined treatment with both trypan blue and neutral red also enhanced the take of BaF1, a benzo(a)pyrene-induced fibrosarcoma. We concluded that both macrophages and NK cells may function as effector cells of an antitumoral surveillance system.
Epstein-Barr virus is an ubiquitous humanpathogenic herpesvirus. It has been identified as the et... more Epstein-Barr virus is an ubiquitous humanpathogenic herpesvirus. It has been identified as the etiologic agent of infectious mononucleosis. In addition it is associated with the cancers nasopharyngeal carcinoma and Burkitt's lymphoma. Like other herpesviruses it infects cells in a lytic way or it persists in a latent state. Classically, the serologic diagnosis of Epstein-Barr virus infections is done by the agglutination of sheep erythrocytes according to Paul and Bunnell as a rapid testing method, and with the immunofluorescence assay. Lately, also the enzyme linked immunosorbent assay using recombinant viral antigens is used for Epstein-Barr virus diagnostics.
We report here the unexpected biological behaviour of the transplantable MC29 virus-induced hepat... more We report here the unexpected biological behaviour of the transplantable MC29 virus-induced hepatoma. This neoplasm, originating from an inbred white Leghorn (Duke) chicken, is maintained in our laboratory by serial in vivo passages in Hunnia hybrid chickens allogeneic to the original host. More than 80% of the tumours developing after subcutaneous inoculation of 3 x 10(6) hepatoma cells into newly hatched chickens grew progressively, while after injection of the same number of cells into 7 days old birds regressive tumour growth was observed. Transplantation from the allogeneic hosts into 7 days old inbred white Leghorn (Duke) chickens also resulted in regression of tumours in the great majority of cases. After inoculation to xenogeneic Japanese quails, progressor tumours developed in both two weeks old and adult birds with a dramatic increase of the frequency of liver metastases. Transplantation to another xenogeneic host, the turkey, revealed an age-related resistance similar to that of Hunnia hybrid chickens.
The effect of syngeneic mouse peritoneal cells (PC) on the growth of four different transplantabl... more The effect of syngeneic mouse peritoneal cells (PC) on the growth of four different transplantable tumours was studied in adoptive transfer experiments (Winn's test). PC from unstimulated mice did not influence the growth of a benzpyrene induced fibrosarcoma (BaF1) and a methylcholantrene induced mastocytoma (P815), but significantly enhanced the growth of a spontaneous adenocarcinoma (Sp4) and Lewis lung carcinoma (LL). PC induced by a single injection of thioglycollate did not influence, whereas PC elicited by proteose peptone markedly enhanced the growth of BaF1 fibrosarcoma. The enhancing effect of peptone induced PC was diminished by a single intraperitoneal dose (100 micrograms/mouse) of polyinosinic-polycytidylic acid (poly I:C) given after peptone injection. Transferring PC obtained after a single injection of poly I:C (100 micrograms intraperitoneally) resulted in retardation of growth of BaF1 fibrosarcoma and Sp4 adenocarcinoma or in a marked decrease in their take depending on the PC/tumour cell ratio. The effector cells involved in the protective effect proved to be different, using these two tumour models. Lewis lung carcinoma and P815 mastocytoma proved to be insensitive to poly I:C-stimulated PC.
Tumours of aged Balb/c mice developed without any conscious experimental interference were excise... more Tumours of aged Balb/c mice developed without any conscious experimental interference were excised and retransplanted to the autochtonous hosts. The autotransplantation resulted in tumour take after a prolonged period of latency or in no take for an extended period of observation (more than 80 days) in 6 out of 19 cases. This can be regarded as a sign of antitumoural resistance, although it seems to be ineffective against development of recidives and metastases or second tumours. The sensitivity of the autotransplantation method in detecting antitumoural resistance was compared to that of the transplantation-excision-retransplantation assay using a benzpyrene induced Balb/c fibrosarcoma; the autotransplantation method proved to be less sensitive. According to these data the existence of some kind of resistance against spontaneous tumour cells cannot be excluded.
Our earlier space experiments demonstrated that the interferon production of human lymphocytes in... more Our earlier space experiments demonstrated that the interferon production of human lymphocytes in microgravity is 4-8 times higher than those of the synchronous ground controls in vitro (Talas et al. 1983). These data suggested that the microgravity has a significant effect on cells. Since the possibilities to perform space-experiments are very limited and our study raised many interesting questions, we wished to simulate microgravity conditions in our laboratory. For this reason we purchased a Rotary Cell Culture System (RCCS) equipment to study different cell lines and human peripheral blood mononuclear cells (PBMCs) in experimental microgravity conditions. RCCS is a horizontally rotated bubble free culture vessel with membrane diffusion gas exchange. We report here an analysis of TNF-alpha (tumor necrosis factor-alpha) production by human PBMCs (control cultures exposed to simulated microgravity in RCCS). The cells were incubated in the presence or absence of either NDV (Newcastle Disease Virus) or one of the different forms (PHA-M or -P) of Phytohaemagglutinin.
Effect of peritoneal cells (PC) from mice treated with a combination of drugs (indomethacin, poly... more Effect of peritoneal cells (PC) from mice treated with a combination of drugs (indomethacin, poly I:C and Syncumar) on the take of Lewis lung (LL) carcinoma was studied in Winn-type adoptive transfer experiments. Transfer of PC from mice given a single intraperitoneal injection of polyinosinic-polycytidylic acid (poly I:C) or indomethacine or Syncumar (100 micrograms of each) per se did not suppress the take of Lewis lung carcinoma in the recipient mice. PC obtained from mice treated with a combination of indomethacin and poly I:C or poly I:C and Syncumar also failed to inhibit the take of the tumour. In contrast, PC collected from mice after a combined treatment with the three drugs (indomethacin + poly I:C + Syncumar) resulted in a 30-60% decrease in tumour take depending on the tumour cell/PC ratio. This effect could not be observed when a single intraperitoneal dose of cyclophosphamide was administered three days before starting of the combined treatment of the donor mice. The effector cells contributing to the tumour inhibitory effect proved to be nonadherent cells, probably large granular lymphocytes (LGL), as their suppressive effect was abrogated after treatment with the lysosomotrop vital dye neutral red.
We studied the properties of activated peritoneal cells (PC) inhibiting the take of SP4 spontaneo... more We studied the properties of activated peritoneal cells (PC) inhibiting the take of SP4 spontaneous adenocarcinoma and Lewis lung carcinoma in syngeneic mice. Treatment of the poly I:C activated PC from Balb/c mice suppressing the take of SP4 tumour with anti-asialo GM1 antibody and complement before transfer did not affect their tumour-inhibitory potential. PC from Balb/c nude mice treated with poly I:C also inhibited the take of SP4 tumour. Spleen cells from untreated or poly I:C treated Balb/c and Balb/c nude mice, however, did not inhibit the take of SP4 adenocarcinoma. Treatment of peritoneal cells activated by a combination of poly I:C, indomethacin and Syncumar (referred to as "combined treatment") with anti-asialo GM1 antibody and complement could not, or could only partly abolish their tumour-inhibitory potential. The cells mediating the suppression of the take of Lewis lung tumour proved to be Thy-1,2+/-, Lyt-1-, Lyt 2.2- cells. We conclude that the activated peritoneal cells inhibiting the take of SP4 adenocarcinoma and Lewis lung tumour are different from NK cells, NC cells and LAK cells and represent a distinct antitumoural effector cell population.
We compared the effects of various potential effector cells of syngeneic or allogeneic origin on ... more We compared the effects of various potential effector cells of syngeneic or allogeneic origin on the take of a spontaneous adenocarcinoma (SP4) and Lewis lung (LL) carcinoma. As reported earlier, syngeneic resident (non-activated) peritoneal cells (PC) did not inhibit the take of these tumours. On the contrary, transfer of resident PC from allogeneic donors suppressed the tumour take. Syngeneic and allogeneic PC activated by poly I:C or by a combination of indomethacin, poly I:C and Syncumar ("combined treatment") inhibited the tumour take to a similar extent. Syngeneic spleen cells (from untreated mice or from donors underwent "combined treatment") did not inhibit the take of Lewis lung tumour. Transfer of activated allogeneic spleen cells resulted in a stronger inhibition of tumour take than the transfer of resident allogeneic spleen cells.
We have found that genomes of human T cell leukemia-lymphoma virus type I (HTLV-I), BK virus (BKV... more We have found that genomes of human T cell leukemia-lymphoma virus type I (HTLV-I), BK virus (BKV), and a hepatitis B virus (HBV) DNA sequence integrated into DNA of a hepatoma-derived cell line contain binding sites for nuclear factor 1 (NF-1), a cellular protein which binds to adenoviral and putative cellular origins of DNA replication. We suggest that cellular origins of DNA replication acquired by oncoviruses may play a role in malignant transformation after reintegration into the cellular genome by providing new targets for cellular factors initiating DNA replication and by perturbing the temporal order of replication.
Presence of human herpes virus type 8 (HHV8), detected by nested PCR, and expression of Epstein-B... more Presence of human herpes virus type 8 (HHV8), detected by nested PCR, and expression of Epstein-Barr virus (EBV), as assessed by immunochemistry and in situ hybridization, were evaluated in 20 primary non-Hodgkin immunoblastic lymphomas (NHL) of the central nervous system (CNS) from patients who died from AIDS, and in 10 samples of cerebral tissues from patients who died from AIDS, without cerebral lymphoma or Kaposi's sarcoma, as controls. Six lymphomas (30%) contained HHV8 sequences, and 19 (95%) expressed EBV; detection of HHV8 was more frequent in patients with Kaposi's sarcoma, than in other subjects (4/6 versus 2/14). Three (30%) controls contained HHV8 sequences, whereas none expressed EBV. AIDS-related CNS NHL is therefore clearly associated with EBV expression, while the presence of HHV8 appears occasional, probably associated with a low tissue viral load. The high frequency of HHV8 in AIDS-related primary CNS NHL patients with Kaposi's sarcoma suggests that this virus could play a role in the pathogenesis of some cerebral lymphomas.
Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating e... more Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating early, in situ neoplasms. Therefore we studied the effect of inhibitors of macrophage and/or NK cell function on the take of transplantable spontaneous murine tumors in syngeneic mice. The treatment of animals with trypan blue, a selective inhibitor of macrophage function, decreased considerably the period of latency of BSP3 adenocarcinoma; however, it did not increase the take of SP4, SP82 and SP84 adenocarcinomas. The treatment of recipients with neutral red, a selective inhibitor of NK cell function, enhanced the take of SP4 adenocarcinoma. The treatment of mice with agents depressing both macrophage and NK cell function (silica or carrageenan) decreased the both macrophage and NK cell function (silica or carrageenan) decreased the period of latency and/or increased the take of SP4, SP82 and SP84 adenocarcinomas. Carrageenan or a combined treatment with both trypan blue and neutral red also enhanced the take of BaF1, a benzo(a)pyrene-induced fibrosarcoma. We concluded that both macrophages and NK cells may function as effector cells of an antitumoral surveillance system.
Epstein-Barr virus is an ubiquitous humanpathogenic herpesvirus. It has been identified as the et... more Epstein-Barr virus is an ubiquitous humanpathogenic herpesvirus. It has been identified as the etiologic agent of infectious mononucleosis. In addition it is associated with the cancers nasopharyngeal carcinoma and Burkitt's lymphoma. Like other herpesviruses it infects cells in a lytic way or it persists in a latent state. Classically, the serologic diagnosis of Epstein-Barr virus infections is done by the agglutination of sheep erythrocytes according to Paul and Bunnell as a rapid testing method, and with the immunofluorescence assay. Lately, also the enzyme linked immunosorbent assay using recombinant viral antigens is used for Epstein-Barr virus diagnostics.
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