Effect of antitumor agents on the hematology and transplantability of leukemia L-1210.
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Biomedical subjects
Publications and source records attributed to A Goldin.
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The lung colonizing potential of 6 xenografted human colorectal adenocarcinomas following tail vein inoculation of tumor cell suspensions into gnotobiotic 3-4-week-old congenitally athymic mice was investigated. One of the lines, CRCo2, was of particular interest, as apparently distinctive lung colonizing phenotypes, large (greater than 2.5 mm diameter) and small (less than 1 mm diameter) colonies were identified, and variant lines with greater, equal, or lesser ability to grow in the lungs relative to the sc tumor of origin were observed. Another line, CRCo1, was also able to grow well in the lungs following tail vein inoculation, but subsequent cycles of lung tumor recovery and reinoculation i.v. did not result in an enhancement of the tumor's lung colonizing ability relative to the initial i.v. inoculation of the sc carried tumor. Scattered lung colonies were observed following i.v. inoculation of sc carried xenografts in three of the four other lines, but we could not consistently recover lung colonies with these tumors. The data are in accord with the clinical observation that pulmonary metastasis is not a high frequency event in human colorectal carcinoma, illustrating the selective nature and experimental utility of this model of metastasis. Further, there were indications of the inefficient and/or random nature of the metastatic process in some of the tumors, while in others, evidence for both effectively higher and lower metastatic variants were found, as might be predicted in heterogeneous tumor cell populations.
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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.
Levamisole and tetramisole had no antitumor effect against the following transplantable syngeneic murine tumors: L1210 leukemia, P388 leukemia, B16 melanoma, Madison 109 lung tumor, and Lewis lung carcinoma. In the Lewis lung carcinoma system there was no effect on primary tumor growth, metastasis, or survival. Tetramisole had a variable effect on the growth of rhabdomyosarcomas and the survival of BALB/c mice following intramuscular inoculation of Moloney sarcoma virus. In two experiments treatment with tetramisole either prior to or following inoculation of Moloney sarcoma virus increased the number of mice with tumor regression as opposed to progressive tumor growth, incrneased the number of long-term survivors, and prolonged the lifespan of mice that died of tumor. In two further tests neither levamisole nor tetramisole had an effect in this system. In mice immunosuppressed with cyclophosphamide prior to virus inoculation, there was not effect of treatment with levamisole or tetramisole.
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.
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