Ferdinand Lejeune

Human melanoma targeting with alpha-MSH-melphalan conjugate.

A conjugate made of alpha-MSH as a drug carrier and melphalan has been designed in order to target human melanoma cells. Iodination of the alpha-MSH moiety led to a relatively stable tracer which could be easily separated and analysed by reverse phase high pressure liquid chromatography. The conjugate was found to be unstable at neutral pH and a serious denaturation can take place at concentrations exceeding 100 micrograms/ml, especially in plasma. Receptor-mediated cytotoxicity has been shown by the use of cultured alpha-MSH receptor positive/negative cells as well as in vivo B16 murine melanoma model. Body distribution and uptake of the labelled compound were unaltered as compared to those of labelled free hormone. alpha-MSH receptor recognition properties also remained unchanged with a better apparent affinity of the conjugate probably due to the alkylating activity of melphalan itself. Using human melanoma dendritic cells expressing more than 10,000 alpha-MSH binding sites per cell as an in vitro model, we were able to demonstrate higher cytotoxicities as compared to melphalan-treated cells. In contrast, melanoma cells with low receptivity did not show higher cytotoxicity. P388D1 mouse plasmocytoma cells lacking receptors were much more sensitive to melphalan than the conjugate. This phenomenon appeared to be related with the number of binding sites expressed at the time of the experiment as well as cell differentiation and the doubling time. Our findings strongly support the concept of a receptor-mediated cytotoxicity and may enable the in vivo melphalan delivery to target tissues to be increased, achieving an improvement of drug penetration inside melanoma cells.

Surgical management of melanoma: an EORTC Melanoma Group survey

Objectives: The objective of the article is to explore the surgical practices and views in the treatment of melanoma within members and non-members of the EORTC Melanoma Group (MG) during the years 2003–2005. Methods: An e-mail questionnaire (see appendix) developed within the EORTC MG was sent to all melanoma units (MUs) of the EORTC (180) and to selected international centres between 2003 and 2005. The questionnaire investigated the different practices regarding surgical management of melanoma patients at all stages. Results: A total of 75 questionnaires were returned from centres in Europe (70), Israel (3), Australia (1) and the United States (1). Resection margins on primary melanoma vary according to AJCC 2002 staging. Sixty three of 75 MUs perform Sentinel node biopsy. Modified radical neck dissection is performed in 82% of MUs for macrometastases and in 80% of MUs for micrometastases. Most MUs surveyed perform all three levels of Berg axillary dissection whether for macrometastases (79%) or micrometastases (62%). An ilio inguinal-obturator dissection is proposed with macrometastases (41% of MUs), whereas 33% of MUs perform a pelvic dissection only if the Cloquet node is positive. Twenty five of 75 MUs perform an isolated limb perfusion with a therapeutic indication; three also as an adjuvant. The majority of MUs perform surgery for distant metastases including superficial (53 of 75 [71%]) or solitary visceral metastases (52 of 75[69%]) or for palliation (58 of 75[77%]). Conclusion: The adequacy of surgery appears to be the most important milestone in the therapeutic approach of melanoma. Even if surgery is fundamental in the different stages of the disease, there is quite a variability concerning the extension of the surgical treatment related to primary and lymphnodal disease. Phase III randomised trials have shown that wide margins, elective lymph node dissections, and prophylactic isolated limb perfusions have not improved survival and cannot be considered the standard of care in the routine management of primary melanoma. The surgical subgroup of the EORTC Melanoma Group is developing a new version of the surgical survey questionnaire including new treatment modalities like isolated limb infusion and electrochemotherapy, which were not frequently in use some years ago, to obtain new data to be compared to the nearly ten-year-old data.

Melanoma-associated antigens: Prospects for clinical use

Malignant melanomas, although less common than most malignancies, account for 1% of all cancers, and have been the subject of numerous new biological and clinical approaches reported in thousands of publications over the last 15 years. Their strong biological aggressiveness when they attain as little as 1.5 mm in thickness, and their persistent resistance to therapy when they spread - 80% failure to chemotherapy - make malignant melanomas one of the biggest challenges to therapy. A new approach could be the therapeutic use of the immunological reaction of the host. Attempts to demonstrate the existence of melanoma-associated antigens were made in the early seventies and were followed by specific immunotherapy trials, using vaccines prepared from melanoma cells. No definite evidence of melanoma immunogenicity was ever obtained. However, monoclonal antibodies definitely demonstrate the presence of melanoma-associated antigenic structures at the cell surface. In this commentary the following topics will be dealt with: antibodies to melanomas; melanoma antigens; and clinical applications of monoclonal antibodies.

Suppressor cell induction and reticuloendothelial cells activation produced in the mouse by beta 1-3 glucan.

We made a sequential study of the proliferative and functional changes occurring in RE cells after beta 1-3 glucan administration in BDF1, and C57BL mouse. beta 1-3 glucan was administered by single i.v. 50 mg/kg or i.p. 15 mg/kg injection. This successively induced changes in RE cells as follows: on day 3 a rise of acid phosphatase activity in peritoneal macrophages; on day 6 an increase of 3H-TdR incorporation in spleen and peritoneal lymphocytes together with an intense suppression of PHA and LPS responses by spleen cells; on day 10 a 5-fold increase of the percentage of peroxidase rich monocytes in the peritoneum. Thereafter all the values went back to or below control. Our results indicate that beta 1-3 glucan is an in vivo mitogen and a macrophage activator.