The antitumor activity of the polar solvent N-methylformamide (NMF) was evaluated on three lines derived from the Lewis lung carcinoma (3LL), endowed with different metastatic potential. Two administration schedules were tested, these being repeated regimens of NMF (200 mg/kg per dose) for 12 consecutive days, starting 24 h or 6-10 days after tumor implantation (early or late treatment, respectively). The results of the present work can be summarized as follows: (1) NMF regimens did not greatly affect tumor growth behavior of 3LL lines; conversely, they markedly influenced their spontaneous colonizing ability in the lungs, either by delaying early metastatic spread or by reducing the number and size of pulmonary metastases already implanted. (2) A significant increase of NK cell activity during and after early treatment with NMF was observed in the more-metastasizing lines, thus suggesting the possibility of an immunomodulating effect of NMF.

Animals↗

PubMedDate not supplied

Drug-mediated increase of susceptibility of human lung cancer to NK or LAK effector cells.

Previous studies in murine models have shown that in vivo or in vitro treatment of tumor cells with mutagenic triazene compounds (TZC) lead to the appearance of novel drug-mediated tumor antigens (DMTA) capable of eliciting graft resistance in syngeneic hosts. This phenomenon, defined as 'chemical xenogenization' (CX), could be of potential value for immunochemotherapy of human neoplasias. It was also shown that TZC modulate NK sensitivity of murine tumor cells. Therefore, experiments were conducted to evaluate whether susceptibility of a human lung adenocarcinoma cell line (H125) to natural cytotoxic effectors could be affected by treatment with an in vitro active TZC. The results showed that drug treatment of H125 line leads to heritable increase of susceptibility to NK and LAK cells. Moreover, increased binding between effector and drug-treated target cells was observed. Additional studies on HLA antigens showed that changes in HLA-ABC molecule expression were probably not involved in TZC-induced increase of NK/LAK susceptibility. These results suggest that TZC treatment of a human tumor could result in increased expression of membrane structures recognized by natural cytotoxic effector cells. Further studies are required to explore whether these changes are generated by mutational events correlated with TZC-induced CX of human cancer cells.

Antigens, Neoplasm↗

PubMedDate not supplied

Mononuclear cells from peripheral blood of adult donors and from cord blood are equally protected by alpha- and beta-interferons against infection with HTLV-I.

Human mononuclear cells derived from peripheral blood of adult donors (PBMC) or from neonatal cord blood (CBMC) were found to be equally sensitive to the protective effect of alpha- and beta-interferons (IFNs) against the infection with HTLV-I during long-term culture. The effect of IFNs was evidenced by a remarkable reduction of the number of virus-positive cells during culture as evaluated by indirect immunofluorescence for the p19 virus core protein. Moreover, the appearance of p19-positive immortalized clones was inhibited by IFNs in PBMC co-cultures, whereas it was delayed in CBMC cultures. These kinetics are in relation with the higher permissivity of CBMC to the virus in comparison with PBMC, since in CBMC cultures infected cells can be clearly detected starting already 1 week post-infection (p.i.), whereas in PBMC cultures their appearance time is approximately at the 6th week p.i. IFNs acted by 'priming' PBMC and CBMC to an active antiviral competence, since one single treatment with 1000 IU/ml of alpha- or beta-IFN at the onset of the co-culture of mononuclear cells with irradiated virus-donor cells was able to maintain very low levels of infection for approximately 6 weeks in CBMC cultures and at least for 18 weeks in PBMC cultures. As a consequence, it seems likely that IFN action is mediated by the expression of a defined, although not completely identified, set of genes in the host cells.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

An immunopharmacological approach for prevention of retrovirus-associated disease in human pathology.

Retroviruses of the HTLV and HIV subfamilies share a number of similar properties in terms of route of transmission and ultimate targeting to CD4+ T-cells, which results in leukaemic transformation in the case of HTLV and in depletion of CD4+ population and failure of T-helper function in HIV-infected individuals. Both diseases gain poor benefit from therapy at the stage of clinical diagnosis as ATL leukaemia or AIDS, respectively. Therefore the best chances to limit the worldwide distribution of these human retroviruses reside in an effective prevention of viral diffusion, possibly by vaccination, and of the onset of disease in virus-positive subjects. The possibility is discussed of defining protocols to prevent the development of clinical disease. These protocols could be based on pharmacological reconstitution of host's immune reactivity, that is altered early after infection with these retroviruses, and on the control of virus replication by antiviral therapy.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Immuno-chemotherapy of advanced colorectal cancer with alpha-2a interferon and 5-fluorouracil. Immunopharmacological studies.

Twelve patients with metastatic colorectal cancer received alternating cycles of low immunomodulating doses of alpha-IFN + 5-Fluorouracil (5-FU) or 5-FU alone. Hematological, biochemical and physical evaluation showed that both treatment cycles were well tolerated. However, transient fever and moderate flu-like symptoms were observed following alpha-IFN administration. Treatment with 5-FU alone produced long-lasting inhibition of CD8+ T lymphocytes, but did not depress NK activity (NKA). Combined treatment with alpha-IFN produced a short-term increase of NKA and antagonized the effect of 5-FU on CD8+ cells on day 5 of the cycle. Parallel studies on in vitro models showed antiproliferative effects of 5-FU on PHA-stimulated MNC and confirmed the preferential inhibition of CD8+ cells. Pretreatment with alpha-IFN did not reverse the effect of 5-FU on CD8+ lymphocytes, but partially protected MNC from the toxic effects of the drug. This was presumably due to the cytostatic effects induced by alpha-IFN on MNC before exposure to the cycle-specific antineoplastic agent. This investigation suggests that alpha-IFN could play a positive role in immuno-chemotherapy of colorectal cancer through multiple mechanisms not entirely related to direct antitumor effects of the agent.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Drug induced modulation of immune responses in mice: effects of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy).

Graded doses of Cyclophosphamide (Cy) or 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) were given to CD2F1 or C57Bl/6 mice. One, 45 or 60 days later the animals were tested for allograft responses, competence of producing cytotoxic lymphocytes in vitro and lethal graft-versus-host disease (GVHD) in vivo, delayed-type hypersensitivity (DTH) and humoral antibody responses against sheep red blood cells (SRBC). Both agents produced strong inhibitory effects, except for DTH, when given 1 day before the antigenic stimulus. However immunodepression lasted for at least 60 days after DTIC, whereas relatively rapid recovery of immune responsiveness was detected in mice treated with Cy. When Cy or DTIC were given to allogeneic donor mice 1 day before spleen cell transfer, immunodepressed recipients did not undergo GVHD. However when drugs were administered to recipient mice inoculated with allogeneic spleen cells, lethal GVHD occurred when Cy but not DTIC was given to the hosts. DTH responses were potentiated by Cy when the drug was given 1 day before sensitization. In contrast hypersensitivity reactions were not affected by DTIC treatment. It was concluded that DTIC is a potent and long-lasting immunodepressive agent, capable of affecting various T-cell subpopulations and possibly B lymphocytes in mice. Since the drug inhibits immune response when given before the antigenic stimulation, it was suggested that DTIC acts through a mechanism similar to that of alkylating non phase-specific agents.

Animals↗

PubMedDate not supplied

Effect of 4-hydroxynonenal, a product of lipid peroxidation, on natural cell mediated cytotoxicity.

Lipid peroxidation of cell membrane yields a variety of final products whose a quantitatively important component is 4-hydroxynonenal (HNE). Previous studies performed in our laboratory suggest that HNE may play a physiological role in the control of cellular proliferation and/or differentiation. This appears to be further supported by our recent findings showing that pre-treatment of K562 cells with a physiological concentration of HNE leads to a marked reduction of susceptibility of NK cells. The observed regulatory effects of HNE on tumor cell growth and susceptibility to natural immune resistance, led us to try to better understand the immunotoxicological properties of this aldehyde. The present study analyses the effects of HNE on NK-mediated cytotoxicity. Treatment of MNC as effector cells with concentrations of HNE ranging from 0.001 to 1 microM for 1 h, did not produce noticeable effects on NK activity. Therefore, this aldehyde at physiological concentrations is able to differentiate tumor cells and to down-regulate target susceptibility to NK effectors from one side. On the other side, it is not able to modify the efficiency of the NK function. Moreover, HNE concentrations higher than 1 microM showed significant and concentration-dependent inhibition of NK activity. However, this effect is reversible and can be antagonized, at least in part, by treatment of effector cells with HNE in combination with beta-interferon.

Aldehydes↗

PubMedDate not supplied

In vitro effect of hyperthermia on natural cell-mediated cytotoxicity.

It is well known that hyperthermia (HY), which is used for the treatment of cancer, depresses natural cell-mediated immunity in vitro. Experiments were performed to confirm the inhibitory effect of HY (42 degrees C for 1 hour) on natural killer (NK) activity and to evaluate the influence of HY on the generation and cytotoxic activity of interleukin-2 (IL-2)-activated NK cells. Additional experiments were also carried out to evaluate the effect of a simultaneous exposure of effector and target cells to HY. The results showed that HY profoundly reduced the lytic activity of NK cells and demonstrated that this inhibition was transient and not due to an apoptosis-induced reduction of the number of effector cells. Moreover, the exposure of mononuclear cells to HY before IL-2 stimulation did not affect the generation of IL-2-activated NK cells, whereas, the hyperthermic treatment of IL-2-activated NK cells produced a marked reduction of their cytotoxic activity. The results also showed that the simultaneous exposure of effector and target cells to HY, during the cytotoxicity assay, produced a marked reduction of lytic activity of NK and IL-2-activated NK cells, and that this impairment was specific for effector cells. In this context, heat-exposure of target cells alone, did not substantially modify their susceptibility to lysis induced by either NK or IL-2-activated NK cells. These results add further evidence of HY-induced inhibition of natural cell-mediated immunity, and suggest that, in the course of therapeutic HY, immune response could be significantly altered.

Cell Communication↗

PubMedDate not supplied

Effect of 5-fluorouracil on carcinoembryonic antigen expression and shedding at clonal level in colon cancer cells.

BACKGROUND: The carcinoembryonic antigen (CEA) is a tumor marker largely utilized for the detection of minimal disease or as a target of immunotherapeutic approaches. In preclinical models CEA has been found to be up-regulated after exposure of cancer cells to 5-fluorouracil (5-FU). In the present study, the clonal distribution of CEA and its regulation by 5-FU at clonal level was investigated using human HT-29 colon cancer cells. MATERIALS AND METHODS: The extent of CEA expression was measured in terms of: (a) antigen levels on plasma membrane, by flow cytometry; (b) cytoplasm and membrane protein, by Western blot analysis: (c) transcript, by Northern blot analysis; (d) CEA shedding by radioimmunossay. RESULTS: CEA protein and gene transcript were variably expressed among different clones. In all cases 5-FU was able to increase the percentage of CEA-positive cells, the amount of antigen, either in the membrane or cytosolic fractions, and the corresponding transcript. Moreover, a marked increase of CEA shedding was found in drug-treated cells with respect to that of controls. The increase of CEA induced by the antimetabolite was not the result of a selection mechanism based on preferential killing of CEA negative cells. The antimetabolite was capable of enhancing antigen expression also in other CEA-positive tumor cell lines with different basal levels of the marker. CONCLUSIONS: The present findings could be of potential value to increase the sensitivity of diagnostic procedures based on detection of CEA positive tumor cells. Moreover, the antimetabolite might be included in immunotherapeutic protocols to facilitate recognition of CEA-positive cancer cells by immune responses.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Inhibition of antilymphoma allograft response in normal and lethally irradiated mice by cyclophosphamide (NSC-26271) and isophosphamide (NSC-109724).

Cyclophosphamide and isophosphamide (an analog) were tested for their effect on the antilymphoma allograft reaction in normal and lethally irradiated mice. Both drugs were effective in abrogating the classic allograft response if given 1 or 3 days before the tumor challenge. While the drugs also inhibited the hemopoietic-histocompatibily response, they were effective when adminstered 7 days before challenge. It is suggested that the activity of various immunosuppressive agents could be compared for their effect on the hemopoietic-histocompatibility system to select the best agent for transplantation of bone marrow or bone marrow or bone marrow-derived cells. Drug toxicity, as well as the effect of the drugs on humoral response and DNA synthesis, was also compared. While isophosphamide was found to be less toxic than cyclophosphamide, the effect of humoral response and DNA synthesis was comparable.

Animals↗

PubMedDate not supplied

Cytotoxic effects of dacarbazine in patients with acute myelogenous leukemia: a pilot study.

BACKGROUND AND METHODS: Preclinical studies performed in our laboratory showed that mouse leukemias become highly immunogenic following in vivo treatment with Decarbazine. This observation led to a successful immunochemotherapy protocol in mice using Dacarbazine plus cytoreductive chemotherapy. Therefore an in vivo and in vitro pilot study was conducted in patients (pts) with resistant or relapsed acute myelogenous leukemia (AML). The DNA-repair enzyme O6-alkylguanine-DNA-alkyl-transferase (OGAT) and the in vitro chemosensitivity to Temozolomide, a Dacarbazine derivative, were evaluated in leukemic blasts. RESULTS: Nine pts received Dacarbazine (0.4-0.8 g/sqm/day) on days 0, 1 and 2. On day 7, noticeable blast reduction occurred in 4 pts: pt 1 was in partial remission on day 21, pt 6 still showed bone marrow leukemia, pt 8 died of sepsis on day 8, pt 9 is still in aplasia on day 25. Low OGAT levels and consistent sensitivity to Temozolomide in vitro were found in the blasts of pts responsive to Dacarbazine. Subsequently, pts 1-7 underwent Ara-C (1g/sqm/day) plus Mitoxantrone (6mg/sqm/day) treatment for 6 days. Four pts entered complete remission after 27-45 days of aplasia. Failures were due to hypoplastic death, absolute drug resistance, or hypoplasia followed by blast cell regrowth. CONCLUSIONS: These data point out that Dacarbazine can induce a marked reduction of blast cells as well as severe myelotoxicity in leukemic patients.

Antiemetics↗

PubMedDate not supplied

Effect of in vitro interferon treatment on the rapid clearance of murine leukemia cells in vivo.

Previous work showed that interferon (IFN) can protect target cells from NK mediated lysis in vitro. In the present study we investigate the effect of IFN alpha/beta or IFN gamma treatment of three different murine leukemia cell lines. For this purpose FLC-745 (susceptible to the antiproliferative activity of IFN alpha/beta and gamma), FLC-3C18 (IFN alpha/beta -resistant and IFN gamma - susceptible) of DBA/2 origin and EL-4 (IFN alpha/beta - susceptible and IFN gamma - resistant) leukemia of C57B1/6 origin were treated with IFN alpha/beta or gamma in vitro and assayed for their susceptibility to natural resistance measured in vivo as organ rapid clearance 4 hr after iv injection into syngeneic mice. Using young or Poly I:C stimulated hosts, but not mice with low levels of natural resistance (i.e. older animals or mice treated with cyclophosphamide), slower elimination of treated cells was observed with: (a) FLC-745 cells treated with IFN alpha/beta and IFN gamma and (b) FLC 3C18 treated with IFN gamma. Such a delayed clearance was not observed with: (a) FLC-3C18 cells treated with IFN alpha/beta and (b) EL-4 leukemia cells preincubated with IFN alpha/beta or IFN gamma. These results suggest that under selected conditions IFNs can protect leukemic cells from in vivo natural reactivity.

Animals↗

PubMedDate not supplied

The antiproliferative effect of prostaglandin A and J on HTLV-I transformed cells is associated with induction of a heat-shock protein.

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Cell Division↗

PubMedDate not supplied

[Antibacterial activity of antibiotics in experimental encephalitis. An indirect approach to the evaluation of the pharmacokinetic pattern].

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Aminoglycosides↗