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Biomedical subjects

J L Murray

Publications and source records attributed to J L Murray.

At least 91 records · Page 5Linked to original sources
PubMed1990

Imaging with indium111-labeled anticarcinoembryonic antigen monoclonal antibody ZCE-025 of recurrent colorectal or carcinoembryonic antigen-producing cancer in patients with rising serum carcinoembryonic antigen levels and occult metastases.

We tested whether nuclear imaging with indium111 (111In)-labeled murine monoclonal (MoAb) anticarcinoembryonic antigen (anti-CEA) ZCE-025 antibody could detect recurrent disease in patients with a rising serum CEA level but negative findings for computed tomographic (CT) scans of the abdomen and pelvis, chest radiograph, and colonoscopy or barium enema. Twenty patients with a history of completely resected CEA-producing adenocarcinoma (18 with colon cancer, one with breast cancer, and one with Hodgkin's disease) and a rising serum CEA level were given an intravenous infusion of 2 mg of 111In-labeled ZCE-025 mixed with 38 mg of unlabeled ZCE-025. Planar and single-photon emission CT (SPECT) scans were acquired at 72 and 144 hours, and in 19 of the 20 patients these were positive. Of those 19, 13 underwent exploratory surgery, and cancer was found in 10, and two had a diagnostic biopsy, which confirmed cancer. Three patients who had negative laparotomies and all four patients who did not undergo surgery or biopsy were followed radiologically. In all seven, cancer was subsequently detected at the sites suggested by the ZCE-025 scan. Thus, tumor was confirmed in all 19 patients with positive scans. Five of 13 patients who were explored benefited from the study and the exploratory laparotomy, as disease was entirely resected in four or was subjected to definitive radiation therapy to the pelvis in the fifth. In two additional patients who were not explored, MoAb imaging resulted in definitive therapy to regionally confined recurrent disease. 111In-labeled anti-CEA MoAb ZCE-025 scanning in patients with rising CEA successfully imaged metastatic colorectal cancer that eluded detection by other methods and affected the care given to some. These results suggest an important role for 111In-labeled ZCE-025 scanning among patients with rising CEA and otherwise occult metastatic cancer.

Adenocarcinoma↗
PubMed1990

Recombinant alpha-interferon enhances tumor targeting of an antimelanoma monoclonal antibody in vivo.

To determine whether recombinant human alpha-interferon (rIFN alpha A) could enhance tumor uptake of an antimelanoma monoclonal antibody (Mab) 96.5 in vivo, groups of nude mice bearing P97 antigen-positive human melanoma subcutaneous xenografts were given i.m. injections of normal saline or rIFN alpha A daily for 10 days. On day 7, mice received either 5 micrograms of 111In-labeled Mab 96.5 or irrelevant 111In-labeled subclass-matched or non-subclass-matched control Mabs. Animals were killed 72 h later and the percent injected dose per gram (%ID/g) in tumor and normal organs was determined. There was a significant (p less than 0.001) increase in 96.5 in tumors of IFN-treated mice compared to saline-treated mice and mice receiving irrelevant Mabs. There was also a significantly increased uptake of 96.5 in blood, heart, lung, kidney, and muscle of IFN-treated vs. control mice (p less than 0.05). This finding was most likely due to increased antigen shedding since significant differences in %ID/g were not observed between IFN-treated and control mice bearing antigen-negative tumors. Furthermore, P97 content in tumor and tissues of IFN-treated mice bearing melanoma xenografts was significantly higher than in mice without tumors. In summary, IFN enhanced targeting of 96.5 via an antigen-specific mechanism. These data confirm and extend previous studies in other tumor systems, and suggest that clinical trials of Mabs plus IFN might be useful in overcoming poor Mab localization that occurs as a result of antigenic heterogeneity in humans.

Animals↗
PubMed1990

Interleukin-6 induction by a muramyltripeptide derivative in cancer patients.

Interleukin-6 (IL-6) was measured in sera from 26 patients with advanced malignancies before and after an I.V. infusion of muramyltripeptide-phosphatidylethanolamine (MPT-PE) in liposomes. Significantly elevated IL-6 could be measured 2 and 4 h after medium (0.25-0.5 mg/m2) and high (1.0-6.0 mg/m2) doses of the drug accompanied by a rise in body temperature. The biological activity of IL-6 in sera could be inhibited in vitro by monoclonal antibodies against IL-6. Other biological effects of MTP-PE in vivo such as leukocytosis and elevated acute phase reactants are discussed in view of increased IL-6 levels. It is concluded that MTP-PE in liposomes generates increased amounts of IL-6 measurable in serum several hours after administration. IL-6 could therefore play an important role in the biological response modification induced by the drug.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine.

This study examined the antitumor properties of blood monocytes isolated from patients undergoing a phase I trial with liposomes containing muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). Peripheral blood monocytes were isolated from 28 patients receiving twice weekly i.v. injections of escalating doses of L-MTP-PE. Monocytes were harvested before therapy and at various times during the 9-week treatment period. Activation of monocyte-mediated tumorilytic activity was found in 24 of the 28 patients at some time during treatment. Whereas the maximum tolerated dose of L-MTP-PE was 4-6 mg/m2, the optimal biological dose in terms of macrophage activation was 0.5-2.0 mg/m2. The spontaneous secretion of interleukin 1 from monocytes isolated pre- and postinfusion was monitored in two patients. In both patients interleukin 1 secretion correlated with the cytotoxic activity of the monocytes. We conclude that the systemic administration of L-MTP-PE can render the blood monocytes of cancer patients tumor cytotoxic. Since L-MTP-PE is an immunomodulator devoid of direct antiproliferative effects on tumor cells, the data suggest that future clinical trials be conducted using the optimal biological dose rather than the maximum tolerated dose.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Lack of comparability between binding of monoclonal antibodies to melanoma cells in vitro and localization in vivo.

The affinity and specificity of monoclonal antibodies (MAbs) to tumor-associated antigens are often determined by in vitro assays. The specific binding of two anti-human melanoma antibodies (96.5 and ZME-018) and a control antibody (ZCE-025) to three human melanoma cell lines (DX3, A375-M, and Hs294t) was examined under in vitro conditions and compared to in vivo localization of 111In-labeled antibodies to the same cells growing as solid tumors in the subcutis of nude mice. The in vitro binding of the specific MAbs to the tumor cells did not predict in vivo localization. Under in vitro conditions, MAb ZME-018 bound to all three cell lines at levels exceeding that of 96.5, yet ZME-018 did not show superior localization to subcutaneous tumors. MAb 96.5 bound to cultured DX3 cells at levels exceeding those observed with A375-M cells. Yet, 96.5 localized better to A375-M xenografts in nude mice than to DX3 or Hs294t xenografts. Antigen expression differed between in vitro and in vivo growing cells, as evidenced by alteration in binding of 96.5 to tumor cells dissociated from solid subcutaneous tumors. Collectively, the data suggest that in vitro parameters do not predict the clinically relevant localization of MAbs to tumors.

Animals↗
PubMed1989

Altered biodistribution of indium-111-labeled monoclonal antibody 96.5 to tumors and normal tissues of nude mice bearing human melanoma xenografts in visceral organs.

Human melanoma xenografts were produced in the subcutis, kidney, cecum and liver of different nude mice. An 111In-labeled anti-(human melanoma) monoclonal antibody (96.5) or an 111In-labeled nonspecific control monoclonal antibody (ZCE-025) was injected intravenously in separate groups of mice. Radioactive antibody accumulation was measured in tumor, blood, viscera, and carcasses. mAb 96.5 targeted specifically to tumor tissue regardless of site of growth. Tumors in the liver exhibited significantly (P less than 0.05) higher tumor-to-blood ratios (45 +/- 6, mean +/- SEM) than xenografts at other visceral organs, the lowest value being found for subcutaneous melanoma (2.6 +/- 0.5). The differences in tumor-to-blood ratio were due to significant alterations of antibody biodistribution, since the actual antibody concentration in the different tumor sites was similar. The percentage of recovered anti-melanoma antibody per milliliter of blood in mice with visceral lesions (4.6 +/- 1.1% ml) was significantly lower than that found in mice with subcutaneous tumors (9.5 +/- 1.4%/ml, P less than 0.05). Moreover, significantly higher levels (18.2 +/- 3.2%/g, 31.0 +/- 5.1%/g, respectively) of the melanoma mAb 96.5 were found in normal liver and spleen tissue recovered from mice with visceral tumors as compared to tissue from mice with subcutaneous tumors (9.2 +/- 0.9%/g, 13.5 +/- 1.9%/g, respectively; P less than 0.05). These results demonstrate that the presence of visceral tumor can significantly affect tumor-to-blood ratios, blood levels, and biodistribution of 111In-labeled mAb 96.5.

Animals↗
PubMed1989

Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection.

Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 x 10(6) units/M2 body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 x 10(6) units/M2. Pharmacokinetic studies indicated a short half-life (T1/2 alpha = 7-23 minutes). At doses over 0.5 x 10(6) units/M2 increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4-8 x 10(6) units/M2 with a lesser increase at 10-14 x 10(6) units/M2 dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.

Drug Evaluation↗
PubMed1989

Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center.

The clinical data that have been accumulated so far suggests a significant influence of IL-2 dose and schedule on the immunobiological effects and clinical toxicities observed with this cytokine. Consequently, the series of Phase I and Phase II clinical trials conducted at the University of Texas M. D. Anderson Cancer Center in patients with advanced malignant melanoma investigating the use of IL-2 in combination with other cytokines, monoclonal antibodies, or ex vivo activated effector cells have used a common dose and schedule of IL-2 administration for which abundant immunobiological information already exists. This approach allows cross-trial comparison of experience with toxicities, immunobiological observations and clinical activity by a group of investigators within a single institution, and more rapid and valid evolution towards combination biological therapy, which preclinical data suggest will have greater activity than single agent therapy.

Biological Factors↗
PubMed1989

Twenty-eight loci form a continuous linkage map of markers for human chromosome 1.

We have used a combination of 30 serological, protein electromorphic, and DNA markers defining 28 loci to construct a linkage map of chromosome 1. These markers form a continuous linkage group of 320 cM in males and 608 cM in females; female genetic distances were on average twofold higher than those of males across the map. Among the DNA markers are 10 highly polymorphic markers reflecting loci that contain a variable number of tandem repeats, well distributed over the length of the chromosome, that will be highly efficient anchor points for application of this map to studies of human genetic disease.

Chromosome Mapping↗
PubMed1989

Cost, correlates and effects of malpractice litigation in family practice residency programmes in the United States.

A survey of family practice residency programme directors in the United States was undertaken to look at the impact of malpractice and malpractice insurance on residency education. Of 385 programmes 276 (71.7%) responded to the 20 question survey. The results indicated a mean rate of 0.043 claims per resident or faculty member in the previous year. One-fifth of the respondents did not report the type of malpractice insurance retained for residents and over half did not report the cost of insurance for residents. Current problems with liability were most often related to the region of the country, number of visits to the family practice centre, the number of residents, the number of faculty, the type of faculty employer and the type of resident employer. Programmes which anticipated future problems with liability were most likely to be those with current problems. The areas identified as most concerning to residents included: obstetrics, cost of malpractice insurance, difficulty obtaining coverage, and the general anxiety created by malpractice litigation.

Education, Medical, Graduate↗
PubMed1989

Sequential use of indium-111 labeled monoclonal antibodies 96.5 and ZME-018 does not increase detection sensitivity for metastatic melanoma.

Two indium-111 labeled anti-melanoma murine monoclonal antibodies (MAb), 96.5 and ZME-018, each recognizing separate antigens on melanoma cells, were administered intravenously to 17 patients with melanoma in a sequential fashion to determine whether: 1) additional tumor sites could be imaged with the combination compared to a single Mab; 2) the first MAb influenced the biodistribution and tumor localization of the second; and 3) significantly toxicity occurred with the combination. Patients were randomized to receive either 96.5, followed by ZME-018, ZME-018 followed by 96.5, or each MAb followed by itself (controls). Infusions of the second MAb occurred 10 days after the first infusion. Gamma camera images were obtained 72 hours after each antibody infusion. There were 139 known metastatic sites of which 72 lesions were localized by either MAb for an overall sensitivity of 52%. The detection rate was higher when lesions only greater than 1.5 cm were considered. Imaging results were independent of MAb administration sequence. When ZME-018 was given as the first infusion, when ZME-018 was given as a second infusion (p = NS). However, mean sensitivities using 96.5 as the first or second infusion were 48% and 66% respectively (p = NS). There was not a significant number of sites detected by MAb 2 that were missed by MAb 1. Human anti-murine antibody (HAMA) response occurred in seven of eight patients studied; two patients who experienced toxicity had levels of HAMA greater than 2000 ng/ml. We conclude that the use of these two murine anti-melanoma monoclonal antibodies given in sequential fashion did not significantly change the imaging sensitivity from that seen with each individual antibody. Moreover, with the exception of one patient, mean plasma half-life of the MAb did not change significantly, suggesting that overall clearance mechanisms were not saturated by the consecutive doses of monoclonal antibody or significantly altered by the presence of HAMA.

Adult↗
PubMed1989

Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A in cancer patients: a phase I study.

Twenty-seven patients with metastatic cancer were treated with a daily continuous intravenous (IV) infusion of recombinant human interleukin-2 (rhIL-2) along with daily intramuscular recombinant interferon-alpha-2a (rIFN-alpha-2a) 4 days per week for 4 weeks with repeated treatment after 2 to 4 weeks of rest. The maximum-tolerated dose (MTD) was 3 million U/m2/d of rhIL-2 with 5 to 10 million U/m2/d of rIFN-alpha-2a. The dose-limiting toxicities are moderate hypotension requiring low doses of pressors and chronic fatigue associated with decreased performance status. Other common side effects included fever, chills, fluid retention, nausea/vomiting, erythrodermia, weight loss, elevated liver transminase levels, anemia, thrombocytopenia, and CNS toxic effects. There were seven objective responses among 25 evaluable patients. Four major responses (one complete response and three partial responses) were observed among 10 patients with melanoma treated with the MTD level. These data suggest that for cancer patients, concomitant rhIL-2 and rIFN-alpha-2a therapy is tolerable and has manageable side effects. Further phase II studies will be needed to define the antitumor activity of this combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Health maintenance.

"Health maintenance" includes screening procedures, risk assessment, early intervention, and prevention--primary, secondary, and anticipatory. Guidelines for health maintenance in some age groups are quite well established, especially for children. Although recommendations for older adults may lack complete consensus, there are many activities that are widely accepted and can be employed in every primary care physician's practice. In the words of Anne Somers: "Postponement of dependency and promotion of vitality may be the most important public health challenges of the next two decades." Primary care physicians have the greatest opportunity to meet this challenge through the implementation of specific strategies for health maintenance with patients at every stage of life.

Aged↗
PubMed1988

The differential effect of prenatal care on the incidence of low birth weight among blacks and whites in a prepaid health care plan.

Black infants are born with low birth weights (less than 2500 g) and very low birth weights (less than 1500 g) at twice the rate of white infants. We investigated the effect of prenatal care delivered in a health maintenance organization on the birth weights of black and white infants at normal risk for low birth weight. Using birth certificates for all children born in 1978 in the California Kaiser-Permanente hospitals, we studied data on more than 31,000 black and white newborns whose mothers' ages and levels of education were comparable. The data show that black mothers used prenatal care less extensively and had a higher incidence of infants with low birth weights (8.4 vs. 3.6 percent) and very low birth weights (2.0 vs. 0.7 percent) than white mothers. The difference in the use of prenatal care, however, accounted for less than 15 percent of the difference in the incidence of low birth weight. The rates of low birth weight, very low birth weight, and preterm birth (less than 260 days' gestation) decreased with increasing levels of prenatal care for both blacks and whites. However, increasing levels of care were associated with a greater reduction among black infants than among white infants in low birth weight, very low birth weight, and low birth weight at term (greater than or equal to 260 days' gestation). When we compared mothers who received adequate care with those who received inadequate care, the relative risk of giving birth to a very-low-birth-weight infant was reduced 3.6-fold (95 percent confidence interval, 2.0 to 6.6) for black mothers and 2.1-fold (confidence interval, 1.3 to 3.4) for white mothers; the relative risk of giving birth to a low-birth-weight infant at term was reduced 3.4-fold (95 percent confidence interval, 2.2 to 5.4) for black mothers and 1.6-fold (confidence interval, 1.1 to 2.3) for white mothers. We conclude that even in a population of women at low risk for giving birth to low-birth-weight infants, prenatal care is more beneficial for blacks than for whites.

Black or African American↗