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Biomedical subjects

E Reed

Publications and source records attributed to E Reed.

At least 235 records · Page 13Linked to original sources
PubMed1987

Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy.

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per microgram of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/micrograms of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.

Adult↗
PubMed1986

Perturbation of the immune network in herpes gestationis.

We have studied the development of anti-idiotypic antibodies to HLA and of autoantibodies reacting with alloactivated T lymphoblasts in a woman with herpes gestationis (HG). This primigravida developed an elevated titer of anti-HLA antibodies, (Ab1), in association with a low titer and late appearance of anti-anti-HLA antibodies (Ab2). At delivery she developed only minimal levels of antibodies reacting with autologous T lymphoblasts (T1), sensitized against the immunizing HLA antigens of the child. Her serum reacted, however, with T lymphoblasts, primed in AMLC against autologous T blasts alloactivated in vitro against her husband (T2). Because healthy gravidae do not show such antibodies, it appears that they are peculiar to and may represent a perturbation of the idiotypic network in regard to the immune

Autoantibodies↗
PubMed1986

Quantitation of cis-diamminedichloroplatinum II (cisplatin)-DNA-intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy.

The antitumor activity of cis-diamminedichloroplatinum II (cisplatin) is believed to be related to its covalent interaction with DNA where a major DNA binding product is an intrastrand N7-bidentate adduct on adjacent deoxyguanosines. A novel immunoassay was used to quantitate this adduct in buffy coat DNA from testicular and ovarian cancer patients undergoing cisplatin therapy. 44 out of 120 samples taken from 45 cisplatin patients had detectable cisplatin-DNA adducts. No adducts were detected in 18 samples of DNA taken from normal controls, patients on other chemotherapy, or patients before treatment. The quantity of measurable adducts increased as a function of cumulative dose of cisplatin. This was observed both during repeated daily infusion of the drug and over long-term, repeated 21-28 d cycles of administration. These results suggested that adduct removal is slow even though the tissue has a relatively rapid turnover. Patients receiving cisplatin for the first time on 56-d cycles, and those given high doses of cisplatin as a "salvage" regimen, did not accumulate adducts as rapidly as patients on first time chemotherapy on 21- or 28-d cycles. Disease response data, evaluated for 33 cisplatin-treated patients, showed a positive correlation between the formation of DNA adducts and response to drug therapy. However, more data will be required to confirm this relationship. These data show that specific immunological probes can readily be applied to quantitate DNA adducts in patients undergoing cancer chemotherapy.

Animals↗
PubMed1986

Results of semen cryopreservation in young men with testicular carcinoma and lymphoma.

Sixty-two young men with testicular carcinoma (31 patients) or lymphoma (31 patients) were referred for semen analysis and possible cryopreservation before systemic therapy. Seventy-seven percent of the patients, 24 patients with testicular carcinoma and 24 patients with lymphoma, had semen with a decreased chance for fertility (ie, sperm density less than 20 X 10(6)/mL and/or less than 40% motile sperm and/or decreased sperm motility). A decreased number of motile sperm as well as a poor grade of motility appeared in the majority of semen specimens from both patient groups. However, 14 patients had semen that met our criteria for fertility with sperm density greater than or equal 20 X 10(6)/mL, greater than or equal 40% motile sperm, and motility grade greater than 2. Semen quality appeared to be better in patients referred immediately after diagnosis than in patients in whom there was a delay between diagnosis and referral for semen cryopreservation. Twelve patients with semen meeting our criteria for possible fertility and 42 patients failing our criteria elected to cryopreserve semen. A median of three collections per patient were stored. To date, seven patients have withdrawn semen for artificial insemination by husband attempts, and two of these attempts have resulted in pregnancies. Both attempts involved patients with semen that meet our criteria for potential fertility. In the minority of young men with lymphoma or testicular carcinoma who have good-quality semen, semen cryopreservation can preserve reproductive potential after therapy that might otherwise cause sterility.

Adult↗
PubMed1986

Progress and perspectives of systemic anticancer treatment.

Cancer chemotherapy embodies an expanding breadth of molecular and biological disciplines and is evolving from approaches based solely on DNA synthesis to include approaches based on a vast number of cellular factors that may differ between malignant and normal tissues. These factors include response to growth factors, antigenic determinants on cell membranes, the ability to respond to signals of differentiation and/or proliferation, and the ability to stimulate cytotoxic recognition responses. Concurrently, the use of agents designed to interfere with DNA synthesis has led to a better understanding of the molecular events that cause drug resistance. The use of these drugs demonstrated that mechanisms operating in antimetabolite resistance may be quite different from those operating in resistance to alkylating agents. Further, multiple changes may frequently coexist in the same cells. Conceptual advances in the area of drug resistance continue to support the long-held concept that the probability of cure is greatest when the tumor burden is small. National Cancer Institute efforts in drug discovery are now designed to explore these recent developments using screening systems that employ human tumors that are usually resistant to therapy. This approach is expected to contribute substantially to the ability to cure malignant disease.

Antineoplastic Agents↗
PubMed1985

Thrombocytopenia and laboratory evidence of disseminated intravascular coagulation after shunts for ascites in malignant disease.

Twenty-eight peritoneovenous shunts were placed to relieve ascites in 26 patients with a variety of underlying malignancies. Nine of the patients had documented liver metastases and hyperbilirubinemia. Severe thrombocytopenia with laboratory evidence of disseminated intravascular coagulation (DIC) occurred in four of these nine patients following shunt placement. Relative or absolute thrombocytopenia was also commonly observed in this series. Other complications included pulmonary edema, ventricular tachycardia, culture-negative fever, pneumonia, and late shunt occlusion. Good palliation, with relief of abdominal pain or respiratory compromise, was achieved in 57% of these patients. Our experience suggests that DIC following peritoneovenous shunts in patients with malignancy may be more common than previously reported, although not as frequent as the incidence of DIC associated with shunt placement for cirrhotic ascites. Platelet aggregation or Factor X activation by ascitic fluid and failure of the liver to inactivate activated clotting factors may play a role in this coagulopathy. Because of the risk of potentially fatal DIC, palliative peritoneovenous shunts should be considered with caution in patients with liver metastases and hyperbilirubinemia.

Adult↗
PubMed1985

Polyclonal antibodies to quantitate cis-diamminedichloroplatinum(II)--DNA adducts in cancer patients and animal models.

cis-Diamminedichloroplatinum (II) (cis-DDP), the antitumor drug, is cytotoxic in vitro primarily by binding to DNA and disrupting its normal functions. We have studied cis-DDP modification of DNA in nucleated peripheral blood cells (buffy coat cells) of testicular and ovarian cancer patients receiving cis-DDP chemotherapy, and of untreated controls. Using a highly sensitive enzyme-linked immunosorbent assay (ELISA) with an antiserum specific for the bidentate intrastrand N7-deoxyguanosine adduct, blood cell DNA was assayed at multiple times during courses of cis-DDP treatment. A total of 138 samples were analyzed from 54 individuals. Of these, all samples from 18 untreated controls were negative, while 44 out of 120 samples from cis-DDP patients were positive. Testicular and ovarian cancer patients receiving chemotherapy on the first course, and given cis-DDP in 21- or 28-day cycles (five days of drug infusion followed by two or three drug-free weeks) accumulated cis-DDP-DNA adducts in blood cell DNA as a function of dose. Patients receiving their first course of cis-DDP on 56-day cycles and those given high doses of this drug after failing other chemotherapy showed much slower adduct accumulation than patients receiving their first course on 21- or 28-day cycles. Adduct accumulation, in positive patients, occurred both as a function of total cumulative dose and with increasing cycle number, suggesting that adduct removal took at least a month in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Idiotypic network regulations of immune responses to HLA.

The development of antiidiotypic autoimmunity with respect to HLA alloantigens provides an attractive explanation for the phenomenon of maternal tolerance to the fetus and for the tandem selection of two antagonistic traits, major histocompatibility complex polymorphism and alloreactivity. We have demonstrated that both T and B lymphocyte responses to allogeneic HLA antigens are subjected to feedback regulation by autologous antiidiotypic immunity. Idiotypic receptors for the alloantigen expressed by T lymphocytes induce antiidiotypic antibodies that are readily detectable in serum during pregnancy, and antiidiotypic T cells that can be revealed in the autologous mixed lymphocyte culture system. Such antiidiotypic T cells and antibodies inhibit specifically the alloimmune function of autologous T cell lines. Similarly, antiidiotypic antibodies (Ab2) to HLA antibody molecules (Ab1) block the binding of the latter to the immunizing HLA antigen. The prevalence of Ab2 over Ab1 during pregnancy may explain the maternal tolerance to the fetus.

Animals↗
PubMed1984

Modulation of T-cell antigen receptor on lymphocyte membrane.

A mouse monoclonal antibody, Mo. Ab. 108.45, detecting cell-surface determinants associated with the T-cell receptor for alloantigen was produced by immunizing mice with an alloreactive human T-cell clone and fusing the splenocytes with the NS1 plasmocytoma. This Mo. Ab. reacts with the immunizing T-cell clone but not with autologous or allogeneic lymphocytes, lymphoblasts or monocytes; stimulates the proliferation of the immunizing T cells in the absence of the alloantigen; inhibits the response to the specific stimulator; and precipitates a disulfied linked heterodimer composed of two distinct glycoproteins of molecular weights 40000 and 46000. The receptor molecule detected by Mo. Ab. 108.45 modulates on the surface of the cells, reaching the highest levels 5 days following exposure to the specific stimulator. The receptor-associated molecule detected by Mo. Ab. 108.45 was expressed by T-cell clones obtained independently in two different mixed lymphocyte cultures between the same responder and stimulator.

Antibodies, Monoclonal↗
PubMed1983

Anti-idiotypic antibodies to anti-HLA receptors induced by pregnancy.

We have previously shown that lymphoblasts alloactivated in vitro acquire the capacity of stimulating the autologous mixed lymphocyte response. This response is anti-idiotypic in nature because lymphocytes so primed display accelerated memory responses only when restimulated by autologous lymphoblasts that have been alloactivated against the same HLA-DR antigen. Based on this observation we have postulated that the absence of HLA antibodies in alloimmunized human subjects may be due to the development of autoantibodies that react with the anti-HLA receptors expressed by primed lymphocytes or by anti-HLA antibodies or both. This hypothesis has been confirmed in the present investigations which show that sera from parous women react with autologous T lymphoblasts primed in 5-day mixed lymphocyte culture against their husband-i.e., with lymphoblasts expressing receptors for the immunizing donor. Anti-HLA receptors expressed by T and B lymphocytes seem to share serologic determinants because sera that bind to autologous alloactivated lymphoblasts are also capable of inhibiting the anti-HLA activity of autologous and homologous sera. Auto-anti-idiotypic antibodies inhibit the autologous mixed lymphocyte response to autologous alloactivated lymphoblasts, a phenomenon whose in vivo correlate may reside in autoinhibition of anti-HLA antibody formation and of allograft immunity. Because auto-anti-idiotypic antibodies were found in sera from all parous women tested, the hypothesis that nonresponsiveness to alloantigens exists as a state per se is not likely. The passive transfer of antireceptor (idiotype) immunity by use of antibodies from pregnant women's sera may provide a powerful tool for specific suppression of allograft rejection.

Antibodies, Anti-Idiotypic↗
PubMed1983

Influence of race on the predictability of mixed lymphocyte culture identity by HLA-DR matching.

HLA-DR-identical North American individuals of Caucasian, black, and Asian Indian origin were tested in checkerboard mixed lymphocyte cultures (MLCs) and the distribution of negative (weak), intermediate, and positive (strong) MLC reactions was determined using the linear clustering analysis program. Overall, the data show that the frequency of weak MLC reactions is significantly higher when the HLA-DR-identical responder-stimulator pair derives from the same ethnic group than when they are of different ethnic origin. Caucasians responded stronger to blacks than to Asian Indians; blacks responded stronger to Asian Indians than to Caucasians, while Asian Indians responded stronger to blacks than to Caucasians. The fact that the frequency of MLC identity is greater among HLA-DR-identical individuals of similar as opposed to different ethnic origin suggests that the predictability of successful transplants by HLA-DR matching may be also influenced by the ethnic background of the donor.

Black People↗