Tumor‐cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small‐cell lung carcinoma

Brezicka, Fred-Thomas; Holmgren, Jan; Kalies, I.; Lindholm, Leif

doi:10.1002/ijc.2910490619

Cited by 20 publications

(13 citation statements)

References 27 publications

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“…The fact that it is an exclusively antigen expressed on SCLC cells turns it into an appropriate candidate for therapy. Related to this, two monoclonal antibodies against fucosyl-GM1 (F12 and 15) induced CDC and ADCC in fucosyl-GM1 expressing cell lines in vitro , and also conferred protection against tumor engraftment in a mouse model (103). In clinical trials of immunization with fucosyl-GM1-KLH conjugate, SCLC patients demonstrated serological IgM and IgG responses against fucosyl-GM1 and in vitro CDC of fucosyl-GM1 positive cell lines (104).…”

Section: Immunotherapies Using Ganglioside Fucosyl-gm1 As the Targetmentioning

confidence: 94%

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

et al. 2013

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Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.

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Section: Immunotherapies Using Ganglioside Fucosyl-gm1 As the Targetmentioning

confidence: 94%

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

et al. 2013

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“…Since fucosyl GM1 is abundantly present on SCLC cells in clinical tumor specimens, SCLC cells would have been a more relevant target in this study. However, the expression of fucosyl GM1 on SCLC cells cultured in vitro is very heterogeneous on the cell lines hitherto available [18,20]. Work is in progress to identify SCLC cell lines that have homogeneous expression of fucosyl GM1 to be used for further studies.…”

Section: Discussionmentioning

confidence: 99%

“…A large number of studies have shown that MAbs are able to activate complement in vitro resulting in the death of tumor cell targets [20,26,27]. The mechanisms that lead to cell death are thought to be mediated by the formation of complexes of the late complement factors, C5b-C9 (membrane attack complex) [28] which are inserted into the cell membrane resulting in a disturbance of intracellular homeostasis finally leading to cell lysis and death.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesize that additive, and perhaps synergistic, cytotoxic effects can be achieved using combinations of chemotherapy and complement-activating MAbs directed against several antigen systems. In the present study, we have tested this hypothesis in vitro using a murine IgG3 MAb (F12) directed against fucosyl GM1 [15,16], a prominent ganglioside on SCLC [17][18][19], and human complement [20] in combination with DOX, etoposide (VP16) and cisplatin (CDDP). Due to the heterogeneous expression of fucosyl GM1 on SCLC cells in vitro [18] we used a rat hepatoma cell line (H4-II-E), which has a homogeneous expression of fucosyl GM1.…”

Section: Introductionmentioning

confidence: 99%

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Supra-Additive Cytotoxic Effects of a Combination of Cytostatic Drugs and Antibody-Induced Complement Activation on Tumor Cells in vitro

Brezicka

Einbeigi²

2001

Tumor Biol

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Chemotherapy with cytostatic and cytotoxic drugs is the main treatment modality for disseminated cancer. However, despite initial clinical responses seen in certain histotypes, such as small cell lung cancer, relapses mostly occur with chemoresistant phenotypes. In order to prolong the relapse-free period, a combination of chemo- and immunotherapy might offer a new treatment strategy. Here, we have tested our hypothesis that complement activation, induced by monoclonal antibodies, in combination with cytostatic drugs may result in additive cytotoxicity in vitro. Doxorubicin, cisplatinum and etoposide were tested in combination with human complement and a murine monoclonal antibody (MAb F12) directed against the tumor-associated ganglioside antigen fucosyl GM1 on a rat hepatoma (H4-II-E) cell line which was used as tumor model. Using the MTT assay to measure cell survival, supra-additive (i.e. synergistic) cytotoxic effects were seen with each of the cytostatic drugs, the strongest being observed with doxorubicin. These results show promise for further research exploring possible prognostically favorable interactions between cytostatic drugs and monoclonal antibodies in the treatment of cancer.

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“…However, it was not until recently that cytotoxic activity was achieved in vivo with mAb against known cluster antigens (cluster w4 and 5A) (95). Brezicka et al demonstrated ADCC against FucGM,-positive cells both in vitro and in vivo (18). The ganglioside FucGMl is found in few normal tissues except the small intestine and pancreas (78).…”

Section: Carbohydrate Antigens As Therapeutic Targetsmentioning

confidence: 99%

Serological tumor markers for small cell lung cancer and their therapeutic implications

Vangsted

1994

APMIS

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Serological tumor markers may become widely used as inexpensive and non‐invasive methods of cancer detection. Markers of current interest for small cell lung cancer (SCLC) comprise enzymes, peptides, proteins, and carbohydrates. None of the serological markers for SCLC have yet proven to be of diagnostic value and at present their use is limited to monitoring disease and indicating prognosis. However, whilst serological markers related to the metabolic state of SCLC cells, such as neuron‐specific enolase, serum thymidine kinase and tissue polypeptide antigen, may only be used for monitoring patients and for estimating prognosis, the other serological markers under current investigation may be used to indicate new treatment forms. Several novel approaches, including interference in the autocrine growth‐regulating loop of SCLC by either peptides or antibodies, have been tried. SCLC is a highly heterogeneous tumor with respect to antigen expression, regulation of growth, and differentiation state. It is therefore important that new interventions are directed against both antigen‐positive and antigen‐negative tumor cells. For instance, radioisotopes or enzymes coupled to antibodies may be effective by exerting toxicity at some distance from the target. Antigens expressed on SCLC cells, such as peptide receptors involved in growth regulation, carbohydrate antigens like Lewis antigens, carcinoembryonic antigen and the ganglioside fucosylGM1, provide potential targets for antibody‐conjugated therapy.

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Tumor‐cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small‐cell lung carcinoma

Cited by 20 publications

References 27 publications

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

Supra-Additive Cytotoxic Effects of a Combination of Cytostatic Drugs and Antibody-Induced Complement Activation on Tumor Cells in vitro

Serological tumor markers for small cell lung cancer and their therapeutic implications

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