The biologic dual effects of anesthesia and surgical treatment in the patient with cancer.
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Biomedical subjects
Publications and source records attributed to J Lundy.
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C57B1/6 mice were given intravenous tumor cells on day O. Mice were then given either a brief exposure to halothane anesthesia or given halothane and then underwent a hind limb amputation. Immune testing was done at varying time intervals and correlated with the development of artificial pulmonary metastases. The effects of a single 15 minute exposure to halothane on the immune system are probably short-lived and no effect on cell-mediated cytotoxicity was seen on day 7, nor was an increase in pulmonary metastases observed. However, when anesthesia was combined with surgery, cell-mediated cytotoxicity was impaired and an increase in pulmonary metastases was seen. The use of thiabendazole (TBZ), an nonspecific immunopotentiator, in the perioperative period restored the cell-mediated cytotoxic response and resulted in a significant decrease in pulmonary metastases.
Thiabendazole (TBZ) appears to be an immunorestorative agent, demonstrating maximum immunopotentiation in the immunosuppressed host. Initial in vivo and in vitro immune studies indicate that the drug is most effective when given 24 hours prior to or at the time of administration of antigen. Single doses are more effective than multiple daily doses. One cell population potentiated by TBZ is the macrophage, either by direct activation or secondary to increased lymphokine production. As an adjuvant to conventional cancer treatment modalities, TBZ needs the same host setting as seen with many immunopotentiators. Tumor bulk must be reduced by the primary modality. A dose schedule must be developed in conjunction with each primary modality employed, ie, timing is critical. As an adjuvant in cancer therapy, the drug is most effective when given every other day. Depending upon the primary modality employed, adjuvant TBZ may require dose adjustment.
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Thiabendazole (TBZ), a new nonspecific immunopotentiator, was evaluated in combination with Cytoxan in the therapy of a syngeneic murine fibrosarcoma. The reduction of tumor burden by chemotherapy was critical in achieving an optimal response from immunotherapy. Eighty-eight percent of the mice that responded to Cytoxan had sustained regression of tumor with TBZ treatment. The response to TBZ was markedly diminished, both in duration and magnitude, in the mice considered to be Cytoxan nonresponders. Timing of immunotherapy was also important. If Cytoxan and TBZ were given simultaneously, growth kinetics similar to those observed with Cytoxan alone were observed. However, if TBZ was given 4 days after Cytozan administration, prolonged regression of tumor was seen. Alone, TBZ was most effective at a dose of 20 mg/kg. However, in combination with Cytoxan the most effective dose was 0.2 mg/kg. The implications of this finding are discussed.
The effect of thiabendazole (TBZ), an anthelmintic, on a mixed leukocyte culture was assessed. Following i.p. administration of TBZ at a dose of 20 mg/kg to C57BL/6 mice, spleen cells were harvested and reacted in a one-way mixed leukocyte culture with irradiated BALB/c stimulator cells. When TBZ was administered 24 hr before the animals were killed, the proliferative response of spleen cells after 5 days in culture was greater than two times that of responder cells from normal, untreated C57BL/6 mice; the reactivity of spleen cells harvested 48 hr after TBZ administration was not statistically different from controls. Although proliferative response of normal responder cells reached a peak on day 6, TBZ treatment 24 hr before the mice were killed caused spleen cells to reach a proliferate peak on day 3. The magnitude of this peak was three times the normal proliferative peak on day 6. The population of spleen cells affected by TBZ is in the plastic-adherent fraction, and the drug effect can be transferred to normal responder lymphocytes by the addition of peritoneal exudate cells from TBZ-treated mice.
This set of experiments was devised to determine the effects of the commonly employed anesthetic induction agent, thiopental, on the incidence of pulmonary metastases in a murine fibrosarcoma system. A correlation was made with cell-mediated immune responses in vivo and in vitro. In two separate experiments, thiopental-treated mice had a significantly increased incidence of pulmonary metastases. This was correlated with an impaired delayed hypersensitivity reaction to the de novo antigen. 2,4-dinitrochlorobenzene (DNCB) and a suppressed mixed leukocyte culture (MLC) reaction. However, if animals were sensitized with DNCB 5 days prior to receiving pentothal, no impairment of DNCB reactivity was noted. This suggests strongly that the observed defect is in the afferent arm of the immune response. Thiopental suppresses cell-mediated immune responses in this system, and the observed biologic consequence is an increase in pulmonary metastases.
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This set of experiments was designed to evaluate the effects of thiabendazole (TBZ), a relatively nontoxic thiazole derivative, on the delayed hypersensitivity response of normal mice, tumor-bearing mice, and mice immunosuppressed by radiation and chemotherapy. Normal mice treated with a single intraperitoneal injection (20 mg. per kilogram) of TBZ given on the day of challenge with 2,4 dinitrochlorobenzene (DNCB) had 41 percent greater swelling of the injected foot pad than did control animals. This increased immune reactivity could be transferred with spleen cells from TBZ-treated animals as well as with macrophages incubated in vitro with TBZ. Mice given sublethal radiation (450 r) had almost complete restoration of the delayed hypersensitivity response (90 percent of control) when treated with TBZ. The immunosuppressive effects of Adriamycin also could be reversed in a similar fashion. It is likely that the immune function of more than one population of spleen cells is amplified by TBZ treatment. The observed effects strongly suggest that thiabendazole may have a role as an adjunct in cancer therapy.
The mortality of spontaneous gastrointestinal perforation in 36 patients with cancer was 84% (30 patients). The main factors responsible for this included failure of recognition, perforation through tumor, advanced uncontrolled disease and multiple organ failure. Six of 19 patients who underwent surgery survived (32%). Five of these patients did not perforate through tumor and their underlying malignancy was in good control. Earlier diagnosis is essential. Prompt surgical intervention and intensive supportive measures are indicated only if additional therapy of the underlying malignancy offers a reasonable chance for continued worthwhile palliation.
The immunologic status of 24 male patients admitted for acute alcoholic detoxification was evaluated by in vivo and in vitro parameters. In vivo reactivity, as measured by skin testing with a denovo antigen, dinitrochlorobenzene, as well as a recall antigen, tuberculin, was inact. However, both qualitative and quantitative defects were seen in vitro in the thymus-derived lymphocyte population. These defects were not seen in recovered alcoholics, that is, they appear reversible. The defects seen in the cell-mediated immunity of alcoholics may, in part, be responsible for the high incidence of head and neck cancer observed in this patient population.
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