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Biomedical subjects

E Bonmassar

Publications and source records attributed to E Bonmassar.

At least 127 records · Page 7Linked to original sources
PubMed1983

Susceptibility of murine lymphoma cells treated with 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide to NK-mediated cytotoxicity in vitro.

Novel drug-mediated tumor antigens (DMTA) have been detected in chemically induced L5178Y lymphoma of DBA/2 origin, following treatment of tumor-bearing hosts with 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DTIC). Studies were conducted on the susceptibility of the DTIC-treated subline, maintained in tissue culture, to NK-mediated cytolysis in vitro. The results of the experiments showed that DTIC-treated lymphoma cells are less susceptible to NK cell lysis than the parental line (i.e. L5178Y); the DTIC-treated lymphoma, maintained in vivo as ascitic form, behaved as the corresponding in vitro line, thus suggesting that NK-resistant phenotype was not dependent upon propagation conditions. The intrinsic susceptibility to cell-mediated lysis of the DTIC-treated tumor was unchanged, as demonstrated by lysis produced by alloimmune cytotoxic cells or by natural cytotoxic mesenteric lymph node effectors. "Cold" competition experiments and target binding assay performed with L5178Y/tc and its DTIC-treated subline showed that DTIC-altered cells are less efficient than the parental line as "cold" competitor cells for NK-mediated lysis and bind less efficiently than L5178Y tumor to NK lymphocytes. These data suggested that the NK resistance of the DTIC-treated lymphoma may result from a failure to bind to effector cells, as a consequence of a profound rearrangement of the cell surface produced by DTIC treatment of cancer cells.

Animals↗
PubMed1983

Relationships among tumor load, route of tumor inoculation, and response to immunochemotherapy in a murine lymphoma model.

The combined effects of nonspecific immunostimulation with Candida albicans (CA) and chemotherapy were studied in (BALB/cCr X DBA/2Cr)F1 and (C57BL/6Cr X DBA/2Cr)F1 mice bearing virus-induced LSTRA lymphomas. Paradoxically, animals treated with a relatively high number of tumor cells responded better to therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than those challenged with a low number of tumor cells. However, the majority of mice subjected to low initial tumor load were cured when they were treated with chemotherapy or chemotherapy plus booster injection of CA at a relatively "late" stage of the disease, i.e., when high tumor load was present in tumor-bearing hosts. It has been shown that this phenomenon, provisionally called high tumor load protection, occurs when the animals are challenged ip but not when they are challenged iv with the tumor and is abolished by total-body gamma-irradiation. Moreover, marked host protection can be attained when immunostimulated mice, inoculated iv with lymphoma cells, are subjected to simultaneous challenge with high inocula of the same tumor ip, followed by BCNU administration. These data stress the importance of the peritoneal cavity for successful CA plus drug treatment and suggest that optimal tumor "antigen load" should be present at the time of CA and/or BCNU administration.

Animals↗
PubMed1983

Drug-induced immunogenic changes of murine leukemia cells: dissociation of onset of resistance and emergence of novel immunogenicity.

n vivo exposure of tumor-bearing mice to the antineoplastic agent 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DTIC) results in increased immunogenicity of tumor cells, an event often referred to as "chemical xenogenization" (CX). To verify the hypothesis of DTIC-induced somatic mutation(s) as the major mechanism underlying CX, studies were performed to dissociate CX from the onset of drug resistance, which was invoked in the past as an event leading to selection of preexisting immunogenic clones. Therefore, experiments were done with a DTIC-susceptible tumor line treated with DTIC and quinacrine dihydrochloride (Q), an antimutagenic compound, according to selected experimental schedules. At different transplant generations, the CX and the onset of drug resistance were evaluated. The results show that a) Q does not prevent the onset of DTIC resistance, b) DTIC-resistant clones arising after treatment with DTIC plus Q are not immunogenic, and c) CX is selectively antagonized by Q. The present data confirm that DTIC-induced immunogenicity is not the result of a selection mechanism mediated by the drug and give further support to the hypothesis that the molecular mechanism of CX may be related to somatic mutation(s).

Animals↗
PubMed1983

Immunobiological aspects of the nude mouse model relative to human cancer chemosensitivity tests.

The nude mouse model (NMM) has been proposed for testing chemosensitivity of human cancer cells with encouraging results. However, nude mice cannot be considered as unreactive "test tube" recipients of allogeneic or xenogeneic tissues, since a variety of immunological functions are fully represented in these hosts. In general, graft resistance against tumour cells can be classified as: (a) elicitable responses (ER), thymus-dependent, evoked by tumour-associated antigens; (b) natural resistance (NR), T-independent, not requiring previous exposure to transplantation antigens. Graft resistance may therefore play a substantial role even in the absence of a functional T-cell system. This has been demonstrated in irradiated euthymic mice capable of rejecting Hh-incompatible lymphomas, and in nude mice, where NR-type responses are particularly efficient, either in vitro or in vivo. It is reasonable to assume that these responses could interfere with tumour responsiveness to the chemotherapeutic effects of drugs. In fact, marked synergistic effects have been observed in conventional hosts combining chemotherapy with limited ER, or with Hh-type NR present in lethally irradiated mice. Similar combined effects could occur in nude mice bearing NR-susceptible human tumours in the course of chemosensitivity assays. These considerations have led to the search for privileged sites associated with low levels of NR; previous results show that these responses appear to be substantially absent in the brains of conventional mice and extremely low in the same organ of congenitally athymic hosts. It follows that the brain of the nude mouse appears to be a suitable site for human tumour cell growth, unaffected by or minimally subjected to NR.

Animals↗
PubMed1982

Cellular mechanisms underlying the adjuvant activity of Candida albicans in a mouse lymphoma model.

Inactivated Candida albicans (CA) possesses strong anti-tumor activity when combined with cytoreductive chemotherapy in a mouse lymphoma model. In the present study, experiments were performed in order to elucidate the mechanism(s) underlying CA immunoadjuvant activity. In vivo chemotherapy studies proved that the synergistic anti-tumor effects were lost in athymic (nu/nu) mice and were also abrogated by radiations. In vitro tests did not suggest a major involvement of natural cytotoxic effectors such as macrophages and natural killer cells nor did CA effects appear to be mediated by induction of interferon. It was concluded that the immunoadjuvant activity of CA largely relies on host responses against tumor-associated transplantation antigens with no major involvement of natural resistance immune mechanisms.

Adjuvants, Immunologic↗
PubMed1982

The role of the peritoneal cavity in successful treatment of a murine lymphoma with chemotherapy and non-specific immunostimulation.

The influence of the route of administration and treatment schedule of a yeast immunoadjuvant, Candida albicans (CA) on the degree of success achieved with an immunochemotherapy regimen in a virus-induced murine lymphoma has been evaluated. To this end, histocompatible CD2F1 mice received IP or IV inoculations of LSTRA lymphoma cells and were subjected to various treatments with inactivated CA and bis,1,chloroethyl nitrosourea (BCNU). The results showed that CA may significantly increase the antitumor efficiency of BCNU when (a) the tumor is inoculated IP and not IV; (b) CA is administered before (on day -14) and after (on days +1 and/or day +8) LSTRA challenge; (c) CA is given IP as a post-tumor treatment. To ascertain whether the immunoadjuvant effect was anatomically restricted to the peritoneal cavity (PC), spreading of IP injected lymphoma was studied by means of LSTRA cells labeled with 3-5'iodo-deoxyuridine 125I (125IUdR) and tumor bioassay in spleen, lung, kidney, liver, and PC of recipient mice. The results showed that IP tumor challenge led to early (1 h) generalized neoplasia in both untreated and CA-pretreated hosts. Therefore, the combined antitumor effects of chemotherapy and CA are not restricted to the PC but rather the result of systemic immunity. In conclusion, in our system the PC seems to be a preferential site for eliciting generalized antilymphoma host responses markedly amplified by selected schedules of immunoadjuvant administration.

Adjuvants, Immunologic↗
PubMed1982

Increase of mouse resistance to Candida albicans infection by thymosin alpha 1.

Studies were carried out to assess the ability of thymosin alpha 1 to prolong the survival of mice challenged with Candida albicans. Two- to four-month-old mice were treated with graded doses of thymosin alpha 1 before, after, or before and after intravenous challenge with C. albicans. Significant resistance ot lethal infection was afforded by 100 micrograms of thymosin alpha 1 per kg given before or before and after challenge, whereas no protection was found in mice treated with thymosin alpha 1 administered at any dose level after inoculation. Pretreatment with thymosin alpha 1 also prevented the increased susceptibility to C. albicans infection of mice pretreated with cyclophosphamide on day -6. The results showed that thymosin alpha 1 was capable of protecting untreated or cyclophosphamide-pretreated mice from C. albicans infection at an optimal dose and schedule of administration.

Animals↗
PubMed1982

Intracerebral adoptive immunotherapy of a murine lymphoma antigenically altered by drug treatment in vivo.

Intracerebral tumor neutralization assay and adoptive immunotherapy with in vivo sensitized lymphocytes were done in immunodepressed mice challenged intracerebrally with L5178Y/DTIC lymphoma, a tumor subline antigenically altered by treatment with 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DTIC) in vivo. Primary cytotoxic T-lymphocytes (CTL) were generated in vitro against L5178Y/DTIC cells with the use of splenocytes of histocompatible (BALB/cCr X DBA/2Cr)F1 donors. The extent of antitumor activity of CTL was evaluated by the measurement of tumor cell proliferation in the brain, as judged by the 125I-labeled 2'-deoxyuridine uptake values and by survival times of recipient mice. The results of the experiments showed: a) CTL were highly effective in inhibiting tumor growth when they were injected along with L5178Y/DTIC tumor cells in a Winn-type neutralization assay; b) the tumor inhibition mediated by CTL was specific, since no antilymphoma effects were detected when CTL sensitized against L5178Y/DTIC line were admixed with the parental L5178Y tumor or with other unrelated lymphoma cells; and c) local adoptive immunotherapy with CTL given on day 1, 3, or 5 after the intracerebral challenge with L5178Y/DTIC lymphoma substantially impaired tumor cell proliferation and significantly increased survival times of recipient leukemic mice.

Animals↗
PubMed1981

Combined effects of natural resistance and chemotherapy against a murine lymphoma in lethally-irradiated mice.

Lymphoma EL-4 of B6 origin was inoculated into lethally-irradiated syngeneic B6 or resistant BD2F1 hybrid recipients. Marked impairment of lymphoma cell proliferation (i.e. hybrid resistance, HR) occurred in the spleen but not in the liver or lung of BD2F1 hosts. Treatment with DTIC at the optimal dose of 80 mg/kg i.p. produced inhibitory effects in spleen, liver and lung of young BD2F1 mice, that were much greater than those observed in syngeneic B6 hosts. Increased anti-lymphoma effects for HR and DTIC chemotherapy were not detectable in the liver or lung of old BD2F1 mice or in the spleen, liver or lung of young hybrid recipients depressed for HR by pretreatment with cyclophosphamide. This is the first report on combined antileukemic effects of the host's anti-tumor natural resistance and chemotherapy.

Animals↗
PubMed1981

Impairment of in vitro generation of cytotoxic or T suppressor lymphocytes by Friend leukemia virus infection in mice.

Spleen cells collected from DBA/2 (H-2d) mice inoculated with the polycythemic variant of Friend-Leukemia Virus Complex (FLV-P) were tested for T-dependent immune functions, such as the in vitro generation of cytotoxic T lymphocytes (CTL) and of non-specific T suppressor lymphocytes (STL). CTL were generated against H-2b splenocytes, and STL were obtained following a 5-day lymphocyte culture without stimulator cells. A progressive and severe impairment of the generation of both CLT and STL was found from 2 weeks onward after infection, being almost totally abolished 3-4 weeks after virus challenge. Suppressor cells (SC) capable of inhibiting CTL generation was detected in FLV-P bearing mice. Suppressor activity was unaffected by anti-Thy 1.2 serum and complement but was removed following iron-magnet depletion or passage through nylon-wool column. Moreover complete recovery of the competence of CTL generation was attained when FLV-P infected splenocytes were passed through nylon-wool column. It is concluded that FLV-P infection depresses T-dependent cytotoxic and suppressor responses in mice, by the appearance of non-T adherent phagocytic cells, capable of impairing CTL generation in vitro.

Animals↗
PubMed1981

Transplantation resistance of drug-treated allogeneic mice against murine lymphomas--II. Studies with various tumor-host combinations.

Previous studies showed that treatment of mice with 5(3,3'-dimethyl-1-triazeno)-amidazole-4-carboxamide (DTIC) plus cyclophosphamide (Cy) produce profound depression of classical allograft responses and impairment of endogenous cell proliferation similar to that detectable in lethally-irradiated mice. However efficient localized graft resistance was found in the spleen of drug-treated hybrid or allogeneic mice challenged with lymphoma cells. The present report describes the genetic patterns of this type of natural resistance [hereafter called drug-resistant inhibition of tumors (DRIT) in various tumor-host combinations DRIT was evaluated measuring the extent of 125I-5-iodo-2'-deoxyuridine (125IUdR) uptake in the spleen and liver of leukemic hosts. The results of the experiments performed with two H-2d (i.e. L1210 and LSTRA), one H-2b (i.e. L5MF-22) and one H-2a (i.e. LAF-17) lymphomas inoculated into drug-treated recipients pointed out that: (a) tumor cell proliferation was markedly inhibited in the spleen and weakly or not impaired in the liver of D end Hh-1-incompatible euthymic or nude mice responder for the hh system; (b) no resistance was found in the spleen and liver of Hh-1-compatible B10.A (2R) mice against L5MF-22 lymphoma or of SJL recipients genetically non-responder for the Hh system, against LSTRA cells; (c) splenic resistance against L1210 leukemia was detectable in Hh-compatible B10.A or B10.A (5R) mice; (d) splenic and liver resistance was found in Hh-incompatible but genetically Hh non-responder SJL or C3H mice against L5MF-22 or LSTRA lymphomas, respectively. These results showed that the genetic patterns of the DRIT system parallels the Hh-type immunity in certain tumor-host combinations [(a) and (b)] but not in others [(a) and (d)], as previously detected in lethally-irradiated mice. It is concluded that genetically-controlled lymphoma graft resistance can be retained by mice treated with high doses of antitumor drugs, capable of abrogating classical T-dependent transplantation immunity.

Animals↗
PubMed1981

Inhibition of hybrid resistance to lymphomas by inactivated tumor cells in lethally irradiated mice.

Two murine lymphomas, L5MF-22 of B10.129(5M) (H-2b) origin and P388 of DBA/2 (H-2d) origin, were inoculated into lethally irradiated hybrid (C57BL/6 x DBA/2)F1 (B6D2F1) mice (H-2b/H-2d). Marked localized graft resistance was found in the spleen and occasionally in the liver of recipient mice as a result of a non-T-dependent hybrid resistance (HR). Significant reduction of HR of B6D2F1 mice could be obtained when viable lymphoma cells were inoculated along with inactivated cells of the same tumor or of genetically related leukemias. These results suggest that in vivo competition for HR effectors can take place in mouse spleen and liver leading to a depression of the localized resistance.

Animals↗
PubMed1981

Influence of Ara-C on effector activity of cytotoxic T-lymphocytes in vitro.

Mouse T-lymphocytes carrying the H-2d haplotype were sensitized in vitro against allogeneic spleen cells homozygous for the H-2b haplotype. Cytolytic T-lymphocytes (CTL) were tested in a 4 hr cytotoxicity assay against 51Cr-labeled H-2b RBL-5 lymphoma cells. The cytotoxic activity of CTL was markedly increased by preincubation with Ara-C (1 through 1000 micrograms/ml, 1 hr at 37 degrees C). Limited but significant increase of cytotoxicity occurred when the drug was added to the effector-target mixture, or when target cells were preincubated with Ara-C using the same conditions adopted for the in vitro treatment of CTL. It is suggested that the present findings would contribute to elucidate the mechanism underlying antitumor synergistic effects between host's responses and treatment with antineoplastic agents.

Animals↗
PubMed1981

Drug-mediated increase of tumor immunogenicity in vivo for a new approach to experimental cancer immunotherapy.

In vivo treatment of leukemic mice with the antitumor agent 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) results in early increase of tumor-associated immunogenicity which is expected to evoke host-versus-graft responses. However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug. It follows that the DTIC-mediated increase of tumor immunogenicity effect cannot be of therapeutic value in ordinary conditions. In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells. Infusion of spleen cells into DTIC-treated mice failed to restore graft responsiveness even in allogeneic tumor-host combinations. However, when DTIC treatment was followed by administration of cytotoxic alkylating agents such as cyclophosphamide (CY) or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), graft responsiveness was partially restored upon adoptive transfer of syngeneic splenocytes. (BALB/c X DBA/2) F1 (hereafter called CD2F1) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F1 lymphocytes. The results showed that: (a) DTIC alone or DTIC plus spleen cells produced little or no increase in survival times with respect to untreated controls; (b) DTIC plus CY or BCNU increased survival times to a larger extent; and (c) the adoptive transfer of lymphocytes produced marked protection of leukemic mice when the hosts had been pretreated with DTIC plus CY or BCNU but not with CY or BCNU without DTIC. These data may provide a model for exploiting DTIC-induced increase of tumor immunogenicity for immunochemotherapeutic regimens.

Animals↗
PubMed1980

Transplantation resistance of drug-treated hybrid or allogeneic mice against murine lymphomas. I. Immunopharmacology studies.

Sequential treatment of mice with non-lethal doses of 5(3,3'-dimethyl-l-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy) was found to produce long-term inhibition of endogenous cell proliferation in the spleen and profound impairment of classical allograft responses, similar to that detectable in lethally irradiated mice. Studies were carried out with drug-treated (i.e. treated with DTIC + Cy) conventional or nude mice inoculated with lymphoma cells homozygous for the H-2b or H-2d haplotype. Transplantation resistance in various tumour-host combinations was studied in terms of survival times after tumor challenge or lymphoma cell proliferation in spleen and liver, measured by the uptake of DNA precursor 125I-labelled 5-iodo-2'-deoxyuridine ([125I]dUrd). The results of in vivo transplantation immunity tests or in vitro tests of generation of cytotoxic lymphocytes confirmed that classical T-dependent allograft responses were abrogated by drug treatment of H-2-incompatible hosts. However, localized resistance against lymphoma graft, mainly at spleen level, was found in drug-treated hybrid mice, or conventional and "nude" allogeneic recipients, as judged by [123I]dUrd uptake inhibition. Resistance presumably regulated, at least in part by the Hh (hemopoietic histocompatibility) system, was abrogated by pretreatment with carrageenan, an antimacrophage agent. In addition, treatment with DTIC + Cy did not abrogate NK activity of mice when the in vitro cytotoxicity test was conducted 5 h after Cy administration, i.e. at the time used for tumor challenge in vivo. It was concluded that selected immunological functions (i.e., antilymphoma natural resistance insensitive to DTIC + Cy, called drug-resistant inhibition of tumors, DRIT) possibly of non-T origin, similar to those detectable in lethally-irradiated mice, can be retained by hosts subjected to high doses of certain anti-tumor agents.

Animals↗