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J L Mulshine

Publications and source records attributed to J L Mulshine.

121 records · Page 7Linked to original sources

Markedly different antibody responses to immunized small cell and non-small cell lung cancer cells.

Monoclonal antibodies (MoAbs) to antigens of human small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) were produced from BALB/c mice immunized with either intact cultured cells or membrane preparations from cultured tumor cells. Of 172 MoAbs produced from two NSCLC immunized mice and reactive to NSCLC cells, 137 bound staphylococcal Protein A directly, and only 11 of these 172 MoAbs were significantly reactive with cultured SCLC cells by a solid-phase radioimmunoassay. In contrast, only 16 of 99 MoAbs produced from two SCLC immunized mice and reactive to SCLC cells directly bound Protein A, and most were of an IgM isotype, but 98 of 99 of these antibodies also reacted with cultured NSCLC target plates. Twenty hybridomas producing antibodies reactive with lung cancer cells but not with a B-lymphoblastoid line were cloned. Eleven of these cloned hybridomas were from NSCLC fusions, and nine were from SCLC fusions. When representative hybridoma supernatants were tested against a broad panel of SCLC and NSCLC target plates a similar pattern was seen, with the supernatants from NSCLC-derived hybridomas only reacting strongly to the NSCLC target plates, but the supernatants from SCLC-derived hybridomas always reacting to both SCLC and NSCLC plates. We conclude that the humoral response to immunization with NSCLC cells or membrane preparations is predominantly IgG and that to SCLC is predominantly IgM. Furthermore, many IgG MoAbs reactive with NSCLC lines are poorly reactive with SCLC cells.

Animals↗

Immunolymphoscintigraphy of pulmonary and mediastinal lymph nodes in dogs: a new approach to lung cancer imaging.

Despite improved resolution with new imaging techniques, surgical confirmation of mediastinal lymph node status is often required for reliable staging of patients with non-small cell lung cancer. Recent scintigraphic studies suggest that s.c. administration of radiolabeled antibodies can be more efficient than the i.v. route for targeting regional lymph nodes in animals and humans. To determine if this approach could be applied to the lymphatics of the lung, we injected both specific and irrelevant radiolabeled monoclonal antibodies via a flexible fiberoptic bronchoscope through the mucosa of lobar bronchi in normal dogs. The injected antibodies were expected to drain by way of local lymphatic vessels toward the central lymph nodes, in effect following the same pathway as do cells metastasizing to these nodes during early regional tumor dissemination. To accomplish this, anesthetized dogs were intubated and then coinjected with the two labeled antibodies [600 microCi/100 micrograms (total)] through a fiberoptic bronchoscope. The animals were serially imaged and then autopsied 14-36 h after injection. Individual hilar and carinal nodes contained over 1% of the injected 131I-labeled specific antibody dose and the average selectivity was 2.5:1 with respect to a coinjected irrelevant IgG. Distant organs (mesenteric lymph node, liver, spleen, bone marrow, and lung parenchyma other than the injection site) contained much less radioactivity, and those sites accumulated a greater fraction of the non-specific labeled antibody. The ratio of iodine-131 to iodine-125 counts between hilar/carinal lymph nodes and abdominal lymph nodes ranged from 15:1 to 100:1. These initial studies indicate efficient delivery of antibody to a subset of the regional nodes via pulmonary lymphatics. They suggest the feasibility of this technique which may be of use in the detection and perhaps therapy of human lung cancer metastases in regional lymph nodes.

Animals↗

Indium-111 T101 monoclonal antibody is superior to iodine-131 T101 in imaging of cutaneous T-cell lymphoma.

We have reported that [111In]T101 is highly effective in the detection of cutaneous T-cell lymphoma (CTCL) in nodal and cutaneous (erythroderma and tumor) sites. This study compares the biodistribution of [131I]T101 (1 to 7.1 mg, 2 mCi) in four patients with CTCL; two of these patients also received [111In]T101 (1 mg, 5 mCi). There was rapid clearance of [131I]T101 from whole-body, spleen, liver, and bone marrow, with evidence of loss of 131I tracer from the T101. Lymph node uptake was minimal in three of four patients, and there was no localization in skin lesions. This contrasted with [111In]T101 where there was prolonged retention of activity in these organs and excellent uptake in skin tumors, erythroderma, and lymph nodes. The study showed that [131I]T101 was suboptimal for imaging CTCL patients and demonstrates that the isotope or labeling method can dramatically alter the apparent biodistribution and tumor targeting of a given monoclonal antibody.

Animals↗

Immunolymphoscintigraphy in patients with lymphoma after subcutaneous injection of indium-111-labeled T101 monoclonal antibody.

Indium-111-labeled T101 antibody was injected subcutaneously (s.c.) into the web spaces between the toes of two patients with cutaneous T-cell lymphoma. Computer-assisted gamma scintigraphy was used to measure uptake in lymph nodes and clearance from injection sites. Antibodies passed rapidly and very efficiently from the feet to the inguinal-femoral and iliac lymph nodes after s.c. administration. Contrasting patterns of uptake were seen in patients with different lymph node histology, but additional experience will be required to test the possible correlation with degree of lymph node involvement. This technique provides an efficient, noninvasive method for imaging normal and abnormal lymphoid elements in regional lymph nodes, and it may prove useful in the evaluation of patients with lymphoma or other lymph node disorders.

Antibodies, Monoclonal↗

Radioimmunodetection of cutaneous T-cell lymphoma with 111In-labeled T101 monoclonal antibody.

T101 monoclonal antibody recognizes a pan-T-cell antigen present on normal T cells and also found in high concentrations in cutaneous T-cell lymphoma. We used this antibody, radiolabeled with 111In, in gamma-camera imaging to detect sites of metastatic cutaneous T-cell lymphoma in 11 patients with advanced disease. In all patients, [111In]T101 concentrated in pathologically or clinically detected nodes, including those in several previously unsuspected nodal regions. Concentrations (per gram of tissue) ranged from 0.01 to 0.03 percent of the injected dose and were consistently 10 to 100 times higher than previously reported on radioimmunodetection. Focal uptake was seen in skin tumors and heavily infiltrated erythroderma but not in skin plaques. The specificity of tumor targeting was documented by control studies with [111In]chloride or [111In]9.2.27 (anti-melanoma) monoclonal antibody. Increasing the T101 dose (1 to 50 mg) altered distribution in nontumor tissues. These studies suggest that imaging with [111In]T101 may be of value in identifying sites of cutaneous T-cell lymphoma. In contrast to the targeting of solid tumors, the mechanism of localization appears to be related to binding to T cells, which can then carry the radioactivity to involved sites.

Adult↗

Treatment of non-small-cell lung cancer.

The treatment of non-small-cell lung cancer (NSCLC; including squamous, large-cell anaplastic, and adenocarcinoma) is one of the most frustrating areas in oncology. With the exception of the high cure rates for surgical treatment of truly localized disease, the prognosis for patients with NSCLC is grim. Often rancorous debate has ensued about the best means of exploiting the currently available modalities of radiation therapy and chemotherapy. Recognizing that the effectiveness of the current therapeutic modalities is limited, we will review the treatment results from the past few years that help define where specific treatment options should be used or suggest areas in which to focus future trials. We will also review the implications of current findings in the cell biology of lung cancer as they pertain to the therapy of NSCLC.

Antibodies, Monoclonal↗

Clinical significance of the association of the Von Hippel-Lindau disease with pheochromocytoma and pancreatic apudoma.

Von Hippel-Lindau disease (VHLD) is a rare disorder known to occur with pheochromocytoma. We report a case with this association and also with pancreatic apudoma. We believe that this is the fifth reported case of this triad, which represents an overlap in the multiple endocrine neoplasia (MEN) classification. Many recent reports of overlap of MEN syndromes challenge the validity of this classification. New understanding of the embryologic origin of cells of endocrine organs has led to the elucidation of the APUD (amine precursor uptake and decarboxylation)-neuroendocrine system. Integration of the APUD system may be important to understanding the pathogenesis of the MEN-like syndromes as well as their relationship to the neurocutaneous syndromes. Any endocrine tumor or neurocutaneous syndrome should be evaluated to exclude a spectrum of possible associations.

Adult↗

Immunohistochemical localization of the immunodominant differentiation antigen lacto-N-fucopentaose III in normal adult and fetal tissues.

Monoclonal antibodies were produced by immunizing rats with human small cell lung carcinoma (SCLC) cell lines. Monoclonal antibodies 600D11 and 624A12 were found to be directed against the ceramide pentasaccharide that contains the lacto-N-fucopentaose III (LNFP III) sequence of sugars, an isomer of the Lewis A blood group antigen. LNFP III is an immunodominant antigen whose reactivity is maintained in formalin-fixed paraffin-embedded sections (PS). LNFP III has been recognized in a number of human tumors including: SCLC; adenocarcinomas of the breast, gastrointestinal tract, genitourinary tract, and lung; renal cell carcinoma; neuroblastoma; and myelogenous leukemia. We now report the normal adult and fetal tissue distribution of the LNFP III antigen by immunoperoxidase staining on PS utilizing 600D11 and 624A12. Binding was demonstrated in bronchial epithelium and bronchial glands; squamous epithelium of the esophagus; gastric crypts, duodenal enterocytes and Brunners glands; argentaffin cells; jejunal and colonic goblet cells; pancreatic acinar cells; salivary glands; endocervical and exocervical cells; skin epidermis; myelinated motor fibers; cells of the adrenal medulla and anterior pituitary gland; polymorphonuclear leukocytes (PMNs); tissue macrophages and renal proximal tubules and loops of Henle. Staining was localized to cell membranes and within the cytoplasm, with greatest intensity at the apical and basal portions of the cells. These staining patterns were noted in adult and neonatal tissues, and initial expression could be traced to approximately the second trimester of fetal development. Knowledge of the normal tissue distribution of this immunodominant antigenic determinant may offer insight into its structural and functional role in benign and malignant tissues.

Adolescent↗

Diagnosis and significance of liver metastases in small cell carcinoma of the lung.

One hundred fifty-seven consecutive patients with small cell lung cancer seen at the National Cancer Institute over a four-year period underwent a series of pretherapy liver staging procedures to determine optimal means of detection and prognostic implications of hepatic metastases. Liver evaluation included physical examination, liver function tests, and liver scan (radionuclide or computerized tomography [CT]), as well as percutaneous and/or peritoneoscopy-directed liver biopsy when possible (74%). Liver metastases were detected in 26% of patients. Peritoneoscopy was the most sensitive method of liver evaluation and increased the detection of liver metastases when done in a sequential fashion after percutaneous liver biopsy from 18 to a total of 27 patients. Of the noninvasive procedures, radionuclide and CT liver scan were the most accurate concurring with liver biopsy in 87% of patients but permitting correct discrimination of stage in excess of 96% of patients. The accuracy of this noninvasive procedure was enhanced by an algorithm combining the results of radionuclide liver scan with liver function tests to detect patients with high or low likelihood of liver involvement. The survival and response of patients with liver metastases was significantly worse than those without such metastases with no three-year disease-free survivors among patients with liver metastases.

Actuarial Analysis↗

Analysis of human small cell lung cancer differentiation antigens using a panel of rat monoclonal antibodies.

The antigen expression of human small cell lung cancer (SCLC) was studied using a panel of 21 independent rat monoclonal antibodies. The panel was selected by isolating hybridomas producing antibodies reactive with two SCLC lines but not with autologous B-lymphoblastoid lines. The antibodies were then tested in radiobinding assays against a panel of 17 SCLC lines, 13 non-small cell lung cancer lines, 6 SCLC necropsy specimens, 13 neuroectodermal lines (melanomas, neuroblastomas, glioblastomas), 15 other human lines, the glycolipid extracts of SCLC, human meconium, and human red blood cells. Using immunohistochemical assays, 14 of the antibodies were tested against normal lung, liver, and kidney, and lung cancer biopsies and xenografts. These analyses revealed the following: (a) SCLC elicited predominantly immunoglobulin M antibodies despite hyperimmunization; (b) the 21 antibodies displayed distinct binding and immunohistochemical phenotypes, indicating that they recognized many different epitopes; (c) 14 of the 21 antibodies reacted with glycolipid determinants; (d) the 21 determinants were expressed on over 80% of SCLC cell lines, necropsy samples, and xenografts; (e) the determinants were also expressed on normal adult bronchial epithelium, proximal tubules of adult kidney, and in a few instances on other normal cell types; (f) the antigens were expressed less frequently on nonsmall cell lung cancer samples but did not clearly distinguish SCLC from non-small cell lung cancer; (g) biochemical and morphological variants of SCLC exhibiting more malignant and undifferentiated behavior and containing greatly amplified c-myconcogenes failed to express several determinants or expressed them at lower levels; (h) and finally, while many human cell lines failed to express the antigens including human melanoma and glioblastoma lines, human neuroblastoma lines frequently did express the SCLC antigens. These detailed studies utilizing a panel of distinct monoclonal antibodies define a series of antigens on the surface of the majority of SCLC undescribed previously.

Animals↗

Monoclonal antibodies that distinguish non-small cell from small cell lung cancer.

Two murine IgG2Ak monoclonal antibodies (703D4, 704A 1) were produced and characterized after immunization with a human large cell lung cancer line (NCI-H 157). These antibodies detect different epitopes on 31 kilodalton [35S]methionine incorporating protein(s). Radiobinding and immunohistochemical studies show these antibodies bind to most (11/13) human non-small cell lung cancer (adenocarcinoma, epidermoid, and large cell), but not to small cell lung cancer (0/11) tumors tested. The epitopes these antibodies recognized are also expressed on human melanomas (7/8), two other tumors (osteogenic sarcoma, renal cell carcinoma), but not on many other human tumors (breast, colon, neuroblastoma, lymphoid), and not on a panel of normal adult human tissues. Because the antigen(s) are preserved after fixation and because of their ability to distinguish lung cancer types from each other and normal tissues, they should be of clinical, as well as of biologic interest.

Animals↗

Improved antigen detection in ethanol-fixed cytologic specimens. A modified avidin-biotin-peroxidase complex (ABC) method.

A new amplification technique is described for the detection of small amounts of antigen in ethanol-fixed cytologic specimens and formalin-fixed tissues. By adding a third antibody layer to the already sensitive avidin-biotin immunoperoxidase system, we have demonstrated a considerable increase in both the quantitative and qualitative aspects of this immunostaining method. In evaluating this technique, we employed a previously defined small cell lung carcinoma cell surface antigen system and monoclonal antibodies.

Antibodies, Monoclonal↗

Lipoxygenase inhibitors prevent lung carcinogenesis and inhibit non-small cell lung cancer growth.

The effects of lipoxygenase inhibitors were investigated using human lung cancer cell lines and A/J mice. By RT-PCR, 5-, 12-, and 15-lipoxygenase mRNA was detected in NSCLC cells. NDGA inhibited 5-LO activity in adenocarcinoma cell line NCI-H1264. Using an MTT assay, NDGA, MK591 and AA861 inhibited the growth of NSCLC cell lines tested with IC50 values of 3, 2, and 7 microM, respectively. Using a clonogenic assay, 10 microM NDGA significantly reduced NSCLC colony number. NDGA significantly slowed NSCLC xenograft growth in nude mice. When the tumors were excised and analyzed, nude mice treated with NDGA had significantly more apoptotic figures than did untreated tumors. A/J mice treated with urethane developed adenomas after 4 months and NDGA administration significantly reduced lung adenoma number. These data indicate that lipoxygenase inhibitors inhibit lung cancer growth and prevent lung carcinogenesis.

Adenocarcinoma↗