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Biomedical subjects

M S Mitchell

Publications and source records attributed to M S Mitchell.

At least 109 records · Page 6Linked to original sources
PubMed1980

Opposite effects of different strains or batches of same strain of BCG on in vitro generation of syngeneic and allogeneic antitumor cytotoxicity.

Pretreatment of mice with three batches of BCG Phipps strain 10 days before in vitro immunization of their spleen cells with syngeneic or allogeneic tumor cells augmented the levels of antitumor cytotoxicity (compared to the levels exhibited by in vitro immunized spleen cells from normal mice), whereas pretreatment with another batch of BCG Phipps strain or with a batch of BCG Tice strain suppressed antitumor cytotoxicity. The suppressive effects of these BCG vaccines could not be attributed to route of administration, dose of BCG, or percentage of colony-forming units in an inoculum. The effect of the interval between BCG pretreatment and in vitro immunization on the generation of antitumor cytotoxicity was evaluated; one BCG batch was of special interest, inasmuch as augmented cytotoxicity was obtained when the interval was short and suppressed cytotoxicity was obtained when the interval was long.

Animals↗
PubMed1980

Antitumor effects of doxorubicin against a virally-induced rat osteosarcoma with minimal immunosuppression.

Intratibial inoculation of a Moloney strain of Murine Sarcoma Virus (MSV-M) in neonatal Wistar-Lewis rats produced osteosarcoma in 96% of animals and resulted in a median survival of 20 days. Intraperitoneal (i.p.) administration of doxorubicin (adriamycin) (1-2 mg/kg/d, on day 10-12) resulted in reduced tumor growth and prolonged median survival to 95+ and 64 days, respectively. Higher dose doxorubicin (3-4 mg/kg/d, on day 10-12) caused early lethal toxicity. Autopsy data revealed a characteristic sarcomatous tumor producing osteoid. Gross pulmonary nodules appeared in 30% of both treated and untreated animals. Microscopic evaluation of lung tissue revealed anaplastic tumors without osteoid in as many as 90% of rats. Hepatosplenomegaly was usually present but microscopic sections of the spleen did not reveal tumor. Long bone metastases were increased in frequency in those animals receiving doxorubicin. Cell mediated immunity (CMI) to osteosarcoma cells by peripheral blood lymphocytes of tumor-bearing animals was detectable between days 21-48. This was bimodal with an early peak at day 21 (CMI = 56%) and a late peak at day 39 (CMI = 48%). CMI in rats given 1 mg/kg/d x 3d of doxorubicin was similar, with peak cytotoxicity (CMI = 61%) on day 26. Two mg/kg/d x 3d of doxorubicin did not significantly suppress either the early response (CMI = 50% on day 22) or the second peak (CMI = 38% and 50% on day 40 and 46, respectively). Thus, doxorubicin was effective in decreasing the growth of an MSV-M induced osteosarcoma and prolonging survival in the rat while usually failing to suppress CMI against rat osteosarcoma cells.

Animals↗
PubMed1980

Antigen-antibody complexes generate Lyt 1 inducers of suppressor cells.

Pretreatment of H-2b mice with KCl-extracts of an H-2d tumor (L1210) together with L1210 antibody rendered the mice incapable of mounting an effective immune response to viable L1210 tumor cells. This specific immunosuppression was associated with inhibition of macrophage functions, which could be used to quantitate the level of suppression. Lyt 1 cells (but not Lyt 2 cells) from either the spleen or thymus of mice pretreated with antigen-antibody complexes could adoptively transfer the suppressed state to normal mice. The Lyt 1 cells that transferred the suppression were resistant to low (20 mg/kg) doses of cyclophosphamide (Cy) but required a Cy-sensitive precursor and/or amplifier cell to be activated. Once activated, they required a Cy-sensitive Lyt 1 2 3 acceptor cell in the normal recipient to effectively suppress the adoptive host's macrophages. Our results indicative that immune complexes in concert with a Cy-sensitive T cell generate Cy-resistant Lyt 1 inducers of suppression. These in turn activate normal thymic or peripheral Lyt 1 2 3 acceptor cells, resulting in the generation of effector suppressor T cells. These suppressor cells are most likely the proximate cause of the inhibition of macrophages we have observed in vivo.

Animals↗
PubMed1980

Comparative analysis of the immunosuppressive properties of two antiviral, iodinated thymidine analogs, 5-iodo-2'-deoxyuridine and 5-iodo-5'-amino-2',5'-dideoxyuridine.

5-Iodo-5'-amino-2',5'-dideoxyuridine (AldUrd), given as five single i.p. injections on Days 0 to 4 after antigenic challenge with sheep erythrocytes, had no demonstrable effect on serum hemagglutinin titers in doses as high as 2000 mg/kg/day. This was the maximum feasible single dose, but no 10% lethal dose was determinable. Similarly, 5-iodo-2'-deoxyuridine (IdUrd), 50 mg/kg/day (10% lethal dose), on Days 0 to 4 did not significantly affect this humoral response. However, with a more sensitive assay, immunocytoadherence, reductions in the number of hemagglutinin-forming cells in the spleen were found at several levels of AldUrd and IdUrd, but the same level of inhibition was attained by a course of AldUrd, 2000 mg/kg, or IdUrd, 50 mg/kg. Spleen cell-mediated immunity against lethally irradiated L1210 was measured by 4-hr 51Cr release and 48-hr growth inhibition assays. Both drugs showed dose-related immunosuppression. With AldUrd, 2000 mg/kg/day, and IdUrd, 100 mg/kg/day, on Days 0 to 4, cytotoxicity was inhibited by 35 to 68% and 73 to 90%, respectively. In comparison, a similar course of 1-beta-D arabinofuranosylcytosine, 40 mg/kg/day, completely abrogated both humoral and cell-mediated immunity. When AldUrd and IdUrd were administered on Days -5 to -1, little effect on either type of immunity was found, while pretreatment with the alkylating agent, cyclophosphamide, abolished all T-cell-mediated killing as measured on Day 7. Thus, AldUrd appears to be a very mild and IdUrd a moderate to strong cell cycle-dependent immunosuppressive.

Animals↗
PubMed1980

Metabolism of methotrexate in man after high and conventional doses.

Methotrexate has been found to be extensively metabolized to 7-hydroxymethotrexate in patients receiving conventional doses (less than 10 mg/kg) and high doses (greater than 10 mg/kg). Twelve hours after administration, plasma levels of this metabolite in several patients treated with low doses exceeded those of methotrexate. No 7-hydroxymethotrexate was found in CSF after CNS administration of methotrexate; however, small amounts of the metabolite was found in the CSF after intravenous high dose infusion. We conclude that methotrexate is significantly metabolized in man at all doses used clinically.

Chromatography, High Pressure Liquid↗
PubMed1978

Effect of radiation on cell-mediated cytotoxicity and lymphocyte subpopulations in patients with ovarian carcinoma.

Lymphocyte subpopulations and cell-mediated cytotoxicity (CMI) were studied during radiation therapy in 16 patients with ovarian carcinoma. The total lymphocyte count became depressed in all patients. The depression was more marked among T cells, while the proportion of B cells remained unaffected. In patients with Stage I and II ovarian cancer, CMI was depressed significantly by radiotherapy after 7 days of treatment, remained low at 14 days but recovered despite continuation of radiation. This depression of CMI occurred at a delivered dose of 1,000 rads with subsequent recovery. Patients with Stage III ovarian cancer given pelvic and abdominal radiation were found to have no consistent depression of CMI, a finding similar to that in Stage III ovarian carcinoma patients given chemotherapy.

Adult↗
PubMed1978

Combination chemotherapy for advanced breast cancer: two regimens containing adriamycin.

Forty-eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5-fluorouracil. The response rate in the two-drug treatment group was 50% and in the four-drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p less than 0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate--an important finding in view of the dose-related cardiac toxicity of this agent.

Adult↗
PubMed1978

Systemic bacillus Calmette-Guérin (BCG) activates natural suppressor cells.

Addition of normal C57BL/6 mouse bone marrow cells to an in vitro culture of normal C57BL/6 spleen cells and allogeneic P815-Y tumor cells inhibited the development of cell-mediated immunity. Bacillus Calmette-Guérin (BCG) enhanced the suppressive activity of these bone marrow cells as early as 2 days after its intravenous administration to donor mice and elicited similar activity in the spleen by 7 days. Concomitant with the appearance of suppressor cells in the spleen there was a decrease in bone cell number and an increase in spleen cell number. While normal spleen cells failed to inhibit immunization, spleen cells from thymectomized, irradiated, bone marrow-reconstituted mice were inhibitory. Administration of BCG further increased the suppressive activity of spleen cells in these T cell-deprived mice. From this evidence it appears that systemic administration of BCG activates natural suppressor cells in the bone marrow and elicits suppressor cells in the spleen through the migration and colonization of the spleen by bone marrow elements.

Animals↗
PubMed1977

Identification of squamous cell carcinoma of the head and neck by tissue culture and immunological testing.

We outline the techniques used to successfully grow squamous cell carcinoma in tissue culture, and to test the cellular immunity of the patient by lymphocyte cytotoxicity studies. Lymphocytes cultured with malignant squamous cells killed from 40 to 60 percent of the tumor cells during 48 hours of incubation. These same lymphocytes did not show any killing potential against cultured melanoma cells or against cultured fibroblasts. This demonstrates an immune response that is tumor-antigen specific. There was no evidence of any serum-blocking factor, because the killing potential of these lymphocytes was not significantly altered by the addition of the patients' sera. The implications and potential for early diagnosis made possible by these techniques are discussed.

Adult↗
PubMed1977

Lung carcinoma after radiotherapy and chemotherapy for Hodgkin's disease.

Two patients, aged 29 and 40, with nodular sclerosing Hodgkin's disease, in complete remission for four and six years respectively after intensive radiotherapy and combination chemotherapy, developed carcinoma of the lung in the previous radiation port. Although radiotherapy and chemotherapy can eradicate Hodgkin's disease involving the thorax, this treatment may be associated with the development of a secondary pulmonary malignancy, particularly in a previous radiation port, and several years may elapse before the new tumour becomes evident.

Adult↗
PubMed1977

Effect of chemotherapy and immunotherapy on tumor-specific immunity in melanoma.

The effects of chemotherapy, with nitrosoureas or dimethyl-triazeno-imidazole-carboxamide (DTIC), or immunotherapy with Bacillus Calmette-Guérin (BCG), on cell-mediated immunity (CMI), and serum blocking factor (BF) to melanoma cells were studied in 23 patients. Studies were performed with autologous or allogenic melanoma target cells obtained from recent biopsy, in 16 mm diameter plastic wells. Assays for lymphocyte-mediated cytotoxicity and BF were performed at weekly intervals over the course of 3-4 mo, with some studies extending beyond 3 yr. The specificity of cytotoxicity was good with these methods. Nine patients given nitrosoureas, predominantly methyl-chloroethyl-cyclohexyl-nitrosourea, showed a transient decline in CMI from 42.2 to 14% 3 wk after administration of a single dose of the agent, with a rapid recovery within 1 week. 10 patients given 5-day courses of DTIC at 3-wk intervals showed no decline in CMI after two courses, and 7 of the 10 had no decline even after three courses. Three of the four patients who achieved a remission lost BF previously present: BF reappeared in both patients studied during a subsequent relapse. BCG intradermally or intralesionally elevated CMI within 2 mo after initiation of therapy, but despite continuation of the injections CMI returned to base line in all but two of the nine patients studied. These results indicate that chemotherapy for melanoma with nitrosoureas or DTIC at these schedules is not profoundly immunosuppressive towards tumor-specific immunity, as measured by our procedures. Putative immunotherapy with BCG at these schedules was likewise only transiently stimulatory.

Adult↗