Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro.

The synthetic ether lipids ET-18-OCH3 and BM41.440 and a derivative, hexadecylphosphocholine, were tested for inhibition of [3H]-thymidine uptake into a Chinese hamster ovarian cell line (AUXBl) and its multidrug-resistant subline selected for colchicine resistance (CHRC5). The activity of all three compounds against the multidrug-resistant subline was equal to or higher than that against the parent line. The same result was found for their activity against a human leukemic lymphoblastic cell line (CEM/O) and its methotrexate-resistant subline (CEM/MTX). In contrast, two multidrug-resistant cell lines selected for resistance to Adriamycin, the mouse leukemia cell line P388/ADR and the murine sarcoma cell line S180/ADR, expressed modest cross-resistance to the lipids as measured by thymidine uptake. Experiments performed using the trypan-blue dye-exclusion assay yielded comparable results, although this system revealed a slightly different sensitivity in showing the cytotoxicity of the drugs. By this assay, modest cross-resistance for ET-18-OCH3 and BM41.440 to Adriamycin was found only after 24 h incubation and decreased after 48 h incubation, with almost equal sensitivity to both drugs being shown by the parental (P388/W) and resistant lines (P388/ADR). Furthermore, findings from a human tumor-cloning assay were in accordance with these data, although they did not indicate cross-resistance for the P388/ADR cell line. These results suggest that certain ether lipids and derivatives might represent valuable anticancer drugs warranting further study in the setting of resistant disease.

Unusual course of pulmonary hypertension of vascular origin.

We report a boy with an unusual course of pulmonary hypertension of vascular origin. He suffered from pulmonary perinatal complications due to a Pierre Robin anomaly. Pulmonary hypertension was diagnosed at the age of 18 months. He died from progressive right heart failure at the age of 19 years.

Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin's disease: evidence for distinct cellular origin.

Anaplastic large cell lymphoma (ALCL) is composed of large, frequently bizarre, cells of T- or null-cell phenotype that show a preferential sinusoidal growth pattern and consistent CD30 positivity. Whether these tumors represent a single entity or several, and what the exact cell origin, is controversial. Recently, granzyme B, a cytotoxic granule component, was reported in a small percentage of ALCL, suggesting that some cases may originate from cytotoxic lymphocytes. To further investigate this possibility, we performed an immunohistochemical study of 33 ALCLs of T- and null-cell type, using monoclonal antibodies to cytotoxic cell-associated antigens, including CD8, CD56, CD57, and the cytotoxic granular proteins perforin and TIA-1. In addition, CD4 expression was also evaluated. ALCL cases included 27 classical systemic forms and variants, 3 primary cutaneous (PC) forms, and 3 acquired immunodeficiency syndrome-associated forms. Cytotoxic antigen expression was also studied in 51 cases of Hodgkin's disease (HD) and 17 large B-cell lymphomas (LBCLs) with anaplastic cytomorphology and/ or CD30 positivity. We found that 76% of ALCLs, representing all subtypes except the PC forms, expressed either TIA-1, perforin, or both proteins. Expression of TIA-1 and perforin were highly correlated (P < .001). On the basis of their immunophenotypic profiles, several subtypes of cytotoxic antigen positive and negative ALCL could be recognized. Fifty-five percent of ALCLs (18 of 33) displayed an immunophenotypic profile consistent with cytotoxic T cells. Six cases expressed cytotoxic granular proteins in the absence of lineage specific markers, and one case expressed both T-cell- and natural killer cell-like markers. These 7 cases (21%) were placed into a phenotypic category of cytotoxic lymphocytes of unspecified subtype. Twenty-four percent (8 cases) of ALCLs were cytotoxic granule protein negative. All but one of these displayed a T-cell phenotype. Cytotoxic granule protein expression did not correlate with the presence of the NPM-ALK fusion transcript. Only 10% of the 51 HD cases were found to be TIA-1+, and none expressed perforin. Cytotoxic antigen expression was absent in LBCL. The expression of cytotoxic granule proteins in the majority of ALCL implies a cytotoxic lymphocyte phenotype and suggests that most cases originate from lymphocytes with cytotoxic potential. Furthermore, the demonstration of cytotoxic cell related proteins may be a useful addition to the current panel of antibodies used to distinguish ALCL, HD, and anaplastic LBCL.

Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas.

The paired box containing gene PAX-5 encodes the transcription factor BSAP (B-cell-specific activator protein), which plays a key role in B-lymphocyte development. Despite its known involvement in a rare subtype of non-Hodgkin's lymphoma (NHL), a detailed examination of BSAP expression in NHL has not been previously reported. In this study, we analyzed normal and malignant lymphoid tissues and cell lines, including 102 cases of B-cell NHL, 23 cases of T- and null-cell NHL, and 18 cases of Hodgkin's disease. Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells, less intense reactivity in follicular center B cells, and no expression in cells of the T-cell-rich zones. Monocytoid B cells showed weak expression, whereas plasma cells and extrafollicular large transformed B cells were negative. Of the 102 B-cell NHLs, 83 (81%) demonstrated BSAP expression. All of the 13 (100%) B-cell chronic lymphocytic leukemias (B-CLLs), 21 of (100%) mantle cells (MCLs), and 20 of 21 (95%) follicular lymphomas (FLs) were positive. Moderate staining intensities were found in most B-CLL and FL cases, whereas most MCLs showed strong reactions, paralleling the strong reactivity of nonmalignant mantle cells. Eight of 12 (67%) marginal zone lymphoma cases showed negative or low BSAP levels, and 17 of 24 (71%) large B-cell lymphomas displayed moderate to strong expression. None of the 23 T- and null-cell lymphomas reacted with the BSAP antisera, whereas in Hodgkin's disease, 2 of 4 (50%) nodular lymphocytic predominance and 5 of 14 (36%) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells. Western blot analysis showed a 52-kD BSAP band in B-cell lines, but not in non-B-cell or plasma cell lines. We conclude that BSAP expression is largely restricted to lymphomas of B-cell lineage and that BSAP expression varies in B-cell subsets and subtypes of B-cell NHL. The high levels of BSAP, especially those found in large-cell lymphomas and in some follicular lymphomas, may be a consequence of deregulated gene expression and suggest a possible involvement of PAX-5 in certain B-cell malignancies. This is a US government work. There are no restrictions on its use.