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Biomedical subjects

D Berd

Publications and source records attributed to D Berd.

At least 73 records · Page 4Linked to original sources
PubMed1987

Depletion of suppressor-cytotoxic T-lymphocytes by administration of a murine monoclonal antibody.

We administered anti-Leu 2a, a murine monoclonal antibody to the human suppressor-cytotoxic T-cell subset, to 20 patients with advanced cancer to determine the toxicity and its ability to deplete circulating Leu 2(+) lymphocytes. Four doses were tested, 1, 5, 25, and 100 mg, and the infusion rate varied from 2 to 24 h. Administration of anti-Leu 2a produced rapid (within 4 h) depletion of circulating Leu 2(+) lymphocytes, the magnitude and duration of which were dose dependent: the 1-mg dose caused a less than 50% fall in circulating Leu 2(+) lymphocytes, while the higher doses caused 75-98% depletion of those cells in 10 of 17 patients so treated. The duration of depletion of Leu 2(+) cells was 1-2 days after 5 mg of anti-Leu 2a, 3-4 days after 25 mg, and 4-30+ days after 100 mg. In seven patients (3-5, 3-25, and 1-100 mg), there was persistence of variable numbers of circulating mouse Ig-coated Leu 2(+) cells, possibly indicating impaired capacity to clear these cells. Modulation of the Leu 2a antigen after antibody treatment was not observed. Peak serum levels of anti-Leu 2a were (medians): 5-mg dose = 350 ng/ml, 25-mg dose = 5500 ng/ml, and 100-mg dose = 48,000 ng/ml; murine antibody was detectable in the serum for 7-14 days after the 100-mg dose. All patients had increased titers of antimouse antibody following treatment with peak titers on day 14. The most common toxicity was shaking chills. This occurred within 1.5 h of beginning the infusion, lasted for no more than 30 min, and did not require cessation of the treatment. Anti-Leu 2a administration caused a clinically unimportant, but statistically significant fall in hematocrit (mean = -7%) and platelet (mean = -23%) count and a transient (less than 1 day duration) fall in the total lymphocyte count. Thus, infusion of murine monoclonal anti-Leu 2a can cause substantial depletion of the suppressor-cytotoxic T-cell subset with modest toxicity.

Adult↗
PubMed1987

Elimination of immune suppressor mechanisms in humans by oxazaphosphorines.

The oxazaphosphorine drug cyclophosphamide (CY), has significant immunopotentiating effects. Maguire and Ettore (21) were the first workers to describe CY-mediated immunopotentiation: They reported that guinea pigs treated with CY and then contact-sensitized developed much more intense and prolonged allergic contact dermatitis reactions than did control guinea pigs that had received sensitizer alone. Subsequently, CY was shown to immunopotentiate the acquisition of delayed-type hypersensitivity (DTH) to a variety of antigens and even to syngeneic tissue. The critical factor determining whether CY depresses or potentiates an immune response in experimental animals is the timing of administration of CY and antigen. The dose of CY seems to be much less important. Since 1982, we have performed immunological studies of 74 cancer patients treated with CY. We have tested two doses--1000 mg/M2 and 300 mg/M2, given by rapid intravenous infusion. Using the animal data as a guide, we have elected to administer CY 3 days prior to sensitization with antigen. Our initial two studies were performed with the primary antigen keyhole limpet hemocyanin (KLH): patients with advanced cancer were either sensitized with KLH alone or with KLH 3 days after administration of CY, 1000 mg/M2 ("high dose") or 300 mg/M2 ("low dose"). We found that pretreatment of patients with CY, at either "high" or "low" dose, significantly augmented the development of DTH to KLH. In contrast, the antibody response to KLH was potentiated by pretreatment with "low" dose CY, but not with "high" dose CY. DTH responses to microbial recall antigens (trichophyton, mumps, candida) were not augmented by CY administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1987

Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma.

Twenty-three patients with metastatic melanoma were treated with combination therapy consisting of dacarbazine (220 mg/m2) and cisplatin (25 mg/m2) iv daily for 3 days every 3 weeks, carmustine (150 mg/m2) iv every 6 weeks, and tamoxifen (10 mg) orally twice daily. In 20 evaluable patients, there were no complete responses and ten partial responses. The median remission duration has not yet been reached but exceeds 7 months. Treatment was relatively well tolerated. However, six patients developed deep venous thrombosis, and four of these six suffered pulmonary emboli. Our data support a previous study and suggest that this combination warrants comparison with the active single components in a randomized prospective trial.

Adult↗
PubMed1986

The immunoaugmenting effects of cancer chemotherapeutic agents.

This article has attempted to show that killing of, or damage to, lymphocytes by cancer chemotherapeutic agents does not necessarily lead to immunosuppression, but can just as readily result in immunopotentiation. Although this concept is widely accepted by experimental immunologists, it is not yet fully appreciated by clinical immunologists and clinicians who study cytotoxic agents. The data accumulated so far suggest that for the most extensively studied drug, CY, the most important variable determining whether one observes immunosuppression or immunopotentiation is the timing of the administration of CY and antigen. In animal system, immunopotentiation is produced by administering CY one to four days before antigens, while administration of CY after antigen generally results in immunosuppression. Although in our own studies immunopotentiation was achieved in patients by giving CY three days before antigen, we did not determine whether this interval was optimal, and further clinical study of this variable is needed. The dose of CY is probably less important than the timing. It is premature to speculate on the potential usefulness of CY and other cytotoxic drugs in augmenting immunity to clinically important antigens in patients with cancer or other disease states associated with immunosuppression. However, it is clear that the realization that cytotoxic drugs can be immunopotentiating has given a new perspective on immunoregulation. At the very least, these drugs will be valuable tools in the study of human immune responsiveness and the factors that modulate it.

Adjuvants, Immunologic↗
PubMed1986

Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide.

There is considerable evidence in animal tumor systems that antitumor immunity is modulated by suppressor T-lymphocytes, and that the cytotoxic drug cyclophosphamide (CY) can abrogate that suppression. We measured the acquisition of delayed-type hypersensitivity (DTH) to autologous melanoma cells in 19 patients with metastatic malignant melanoma. The patients were treated with an autologous melanoma cell vaccine, either given alone, or given 3 days after the administration of CY, 300 mg/m2 i.v. The DTH responses of CY-pretreated patients were significantly greater than those of control (vaccine only) patients. Thus, after two vaccine treatments, the median DTH responses (mm induration) were as follows: controls, 4 mm; CY pretreated, 11 mm; P = 0.034, Mann-Whitney U test, 2-tailed. Whereas seven of eight CY-pretreated patients developed DTH to autologous melanoma cells of at least 5 mm, only two of seven controls did so (P = 0.034, Fisher's exact test). Two patients had significant antitumor responses to treatment with CY plus vaccine, consisting of complete disappearance of skin metastases and a pulmonary nodule in one, and regression of s.c. and liver metastases in the other. Both patients remain free of melanoma after 42 and 33 mo, respectively.

Adult↗
PubMed1985

Metastatic uveal melanoma. Pretherapy serum liver enzyme and liver scan abnormalities.

The liver was the organ most frequently involved in 50 patients with primary melanomas of the choroid or ciliary body, who were treated with enucleation or cobalt plaque radiotherapy and who subsequently developed systemic metastasis. Forty-seven (94%) of the patients had clinical or laboratory evidence of liver metastasis. The median survival time following treatment of the primary choroidal melanoma was 28 months (range, 7.7 to 123.1 months). Results of pretreatment studies, including serum liver enzyme levels, liver scans, or both, were abnormal in six (12%) of the patients studied. As a group, the eight patients who died within one year following ocular surgery had a significantly higher prevalence of pretreatment laboratory abnormalities. Extraocular extension of the choroidal melanoma was also present in four (50%) of these eight patients. Conversely, no patient who survived longer than the median survival period (28 months) had abnormal pretreatment laboratory findings.

Adult↗
PubMed1984

Impairment of concanavalin A-inducible suppressor activity following administration of cyclophosphamide to patients with advanced cancer.

We have shown that cyclophosphamide (CY) can augment the development of delayed-type hypersensitivity to a primary antigen in patients with advanced cancer. In the present study, we administered CY (1000 mg/sq m) to 19 patients with advanced, metastatic cancer and monitored the compositional and functional changes in their peripheral blood mononuclear cells. Within 2 days of administration of CY, the lymphocyte count fell significantly (mean decrease = 26.0%) and remained significantly depressed through Day 14 with recovery beginning by Day 21. T- and B-lymphocytes were depleted to about the same degree at each time point. Moreover, there was no selective depletion of the Leu 2(+) (suppressor-cytotoxic) or Leu 3(+) (helper-inducer) subsets of T-lymphocytes. Proliferative responses to mitogens (phytohemagglutinin, concanavalin A, pokeweed mitogen) and to allogeneic cells fell significantly within 1 day of administration of CY and continued to be diminished on Day 2. However, these responses recovered to pretreatment levels by Day 3, and, in some cases, exceeded pretreatment levels on Day 7. Concanavalin A-inducible suppressor activity was also diminished on Day 1 (mean decrease, 23.4%) and Day 2 (mean decrease, 39.2%). However, in contrast to the proliferative responses, suppressor activity continued to be significantly impaired on Day 3 (mean decrease, 31.6%) and only partially recovered by Day 7 (mean decrease, 22.1%). Both concanavalin A-inducible suppression and proliferative responses declined again on Days 14 and 21. Thus, between 3 and 7 days after administration of CY, there appeared to be impairment of nonspecific T-cell-mediated suppressor activity of peripheral blood lymphocytes that was not merely a reflection of impaired lymphocyte function in general. This could account for the augmented delayed-type hypersensitivity responses of CY-treated patients.

Concanavalin A↗
PubMed1984

Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide.

Although cyclophosphamide (CY) is a potent immunosuppressive drug, under the proper conditions, it can potentiate immune responses as well. In past work, we have shown that administration of a commonly used oncostatic dose of CY (1000 mg/sq m) to patients with advanced cancer 3 days before sensitization with the primary antigen, keyhole limpet hemocyanin (KLH), resulted in augmentation of delayed-type hypersensitivity (DTH) but not antibody response to that antigen. The present study was performed to test the immunopotentiation of a lower dose of CY (300 mg/sq m); animal studies and studies of human lymphocytes in vitro suggested that the lower dose might be more effective. Eighteen patients with advanced metastatic cancer were alternately assigned to one of two groups. Sixteen days before CY, one group received KLH and the other group received 1-chloro-2,4-dinitrobenzene (DNCB). CY 300 mg/sq m was given as an i.v. bolus on Day 0. Three days after CY, the patients received KLH or DNCB, whichever they had not received initially. Blood was drawn for antibody titer, and skin testing was performed 14 days after administration of KLH or DNCB. In addition, skin tests to microbial recall antigens were made 2 days before and 17 days after CY. Pretreatment with low-dose CY resulted in significant augmentation of DTH to KLH; thus, the median DTH responses were: KLH alone, 10 mm; and KLH after CY, 27 mm (p less than 0.01). CY pretreatment also resulted in augmentation of the antibody response to KLH. The median total antibody titers (log2 of reciprocal of dilution) were as follows: KLH alone, less than 1; and KLH after CY, 3 (p less than 0.01). All nine CY-pretreated subjects but only 4 of 9 controls developed measurable anti-KLH antibody titers. CY pretreatment neither augmented nor suppressed the 48-hr challenge reaction to DNCB. Moreover, CY had no effect on DTH responses to the recall antigens, dermatophytin, Candida, and mumps.

Adult↗
PubMed1983

Metastatic uveal melanoma. Hepatic cell-surface enzymes, isoenzymes, and serum sialic acid levels in early metastatic disease.

Serum hepatic cell-surface enzymes, isoenzymes, and sialic acid levels may be useful adjuncts in detecting early metastatic disease and in evaluating the tumor burden of patients with uveal melanoma. Hepatic cell-surface enzyme concentrations were elevated in the serum of ten patients with uveal melanoma and liver metastasis and in five patients with other hepatobiliary disorders and in 75 control patients. Five patients in the metastatic group (50%) had serum gamma-glutamyl transpeptidase and 5'-nucleotide phosphodiesterase (5-NPD) bands known to be associated with either primary hepatic carcinoma or carcinoma metastatic to the liver. One patient with uveal melanoma without known metastasis had a positive 5-NPD pattern; metastatic disease was subsequently proved. Higher levels of sialic acid were found in the serum of patients with uveal melanoma and metastatic disease (4 mumole/mL) than in controls (2.4 mumole/mL).

Adult↗
PubMed1981

Differential sensitivity of two murine leukaemia sublines to cytolysis by Corynebacterium parvum-activated macrophages.

We observed the growth of 2 sublines of leukaemia L1210 in histocompatible DBA2 mice given 10(3) cells i.p. and studied the protective effect of Corynebacterium parvum (CP). The growth of subline L1210-M was unaffected by pretreatment with CP or admixture with 10(5) peritoneal cells (PC) from CP-treated mice. In contrast, the growth of subline L1210-C was inhibited; CP pretreatment increased the proportion of long-term survivors (70% vs 20%) and admixture with CP-PC prolonged the survival time (59 days vs 49 days; P less than 0.05). In vitro experiments indicated that Sublines M and C were equally sensitive to cytostasis by CP-PC, as measured in a terminal labelling assay (greater than 90% inhibition of proliferation). However, subline C was much more sensitive to cytolysis (18h 125IUDR-release assay) by CP-PC; percentage specific release from L1210-C was at least 90%, whilst from L1210-M it was generally less than 25%. The differential susceptibility of the 2 sublines to cytolytic PC was maintained through 75 passages in culture. The effector cells were considered to be macrophages, because they were adherent, phagocytic, and sensitive to silica. Cytolysis was unrelated to endotoxin contamination, because it was not inhibited by polymyxin B, and was inhibited by pre-incubating PC in culture medium for 24 or 48 h before adding target cells. Thus the relevance of nonspecific macrophage-mediated cytotoxicity in vitro to tumour resistance in vivo may depend on the strength of the cytotoxic reaction.

Animals↗
PubMed1979

Evaluation of a "nude" mouse-human tumor panel as a predictive secondary screen for cancer chemotherapeutic agents.

Nine established human melanoma tissue-cultured cell lines heterotransplanted in C57BL/6 "nude" mice were exposed to each of 4 chemotherapeutic agents of known clinical activity against human melanoma. Two of the therapeutic agents, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 5-(3,3-dimethyl-1-triazino) imidazole-4-carboxamide (DTIC), are known to be active against human melanoma; the other two, adriamycin and 5-azacytidine, are known to be inactive. Sterile saline served as a control agent. In 2 cell line heterotransplants, the control tumor spontaneously regressed. Of the 7 cell lines that remained for evaluation, 4 were sensitive to DTIC, 1 was sensitive to BCNU, and none was sensitive to adriamycin or 5-azacytidine. These data indicate that the nude mouse-human tumor model may be a predictive secondary screen for cancer chemotherapeutic agents.

Animals↗
PubMed1978

Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma.

Thirty (30) patients with advanced metastatic malignant melanoma refractory to DTIC (NSC-45388) and a nitrosourea were treated with 5-azacytidine (NSC-102816). 5-Azacytidine was administered subcutaneously at a dosage of 100 mg/m2/day for 10 days. Twenty-six (26) patients were evaluable for toxicity and response. Major organ toxicities were hematologic, gastrointestinal, and cutaneous; no antitumor activity was noted.

Azacitidine↗
PubMed1978

Positive phase II trial of dibromodulcitol in patients with metastatic melanoma refractory to DTIC and a nitrosourea.

Twenty-five patients with measurable metastatic melanoma refractory to DTIC and a nitrosourea were treated with dibromodulcitol (DBD). DBD was administered orally at bedtime at a dose of 100 mg/m2/day until hematologic toxicity (a greater than or equal to 50% decrease in the wbc or platelet count) was induced. Five patients experienced clinically useful objective remissions; responding lesions included both soft tissue metastases and visceral metastatic disease. It is concluded that DBD is useful in the treatment of patients with metastatic melanoma and thus joins DTIC and the nitrosoureas as single agents which are active against this malignancy.

Adult↗