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Insulin-like growth factors and their binding proteins in lung cancer Havemann K, Jaques G, Wegmann B, Noll K. Deparrment of Internal Medicine, Division of Hematology/Oncology, Baldingerstrasse. D-3550 Marburg, Germany.

Recent studies have shown that human lung cancer cell lines in tissue culture produce insulin-like growth factor-2 (IGF-2), contain high affinity receptors for IGF-I and IGF-2 and re- spond to exogenously added IGF-I and IGF-2 mainly via the IGF-1 receptor. Based on these findings we and others have proposed the concept that the IGFs may be important growth factors in lung cancer. Recently, it has been demonstrated, that a family of structurally related proteins which specifically bind the IGFs are involved in the modulation of IGF action. Six dif- ferent IGF binding proteins (designated IGFBP-I through IGFBP-6) have been purified and cloned. We have shown that SCLC and NSCLC in culture under serum-free conditions secrete a number of IGFBPs. These IGFBPs are differentially distributed between cell lines and primary tumors of small cell and non-small cell lung cancer cell lines. Treatment of SCLC cell lines with IGFs increased the DNA-synthesis significantly; this effect was reversible by the addition of recombinant IGFBP-2, but not by IGFBP-1.

The influence of various hormones and growth factors on the biosynthesis of the IGFs and their binding proteins was in- vestigated. While no change in the production of the IGFs was found, the expression pattern for IGFBPs was changed by the incubation with IGFs or retinoic acid (RA). With IGF-2 better than with IGF-I we could stimulate the expression of IGFBP-3 significantly, and could inhibit the expression of IGFBP-I, moderately. RA (I PM) on the other side induced an increase of all IGFBPs, mostly pronounced of IGFBP-3.

These results suggest that the IGF activity at the cellular level can be regulated by different secretion patterns of IGFBPs and may have important implications for understanding mechanisms by which IGFs and IGFBPs interact to regulate lung cancer cell growth.

The clinical implication of neuroendocrine markers in non-small cell lung cancer Hirsch FR, Senderovitz T. Department of Oncology, Bispebjerg Hospital, Copenhagen, Denmark.

For many years the non-small cell lung cancer has been con-

sidered as a chemoresistent type of tumor. However, within the last years several pre-clinical and some clinical studies have demonstrated that the distinction between small cell (SCLC) and non-small cell lung cancer (NSCLC) is not black and white. There seems to be a grey zone between those two main types of lung cancer, which might be characterized by the presence of neuroendocrine markers.

From several studies about 20-25% of all NSCLC tumors demonstrates neuroendocrine features with one or more of the following markers: neuron specific enolase (NSE), chromogranin, synaptophysin, Leu 7, neural cell adhesion molecules (NCAM), etc. The present overview will focus on the clinical implication of the presence of NE-markers in non- SCLC tumors.

Two published studies have looked on the clinical impact of the expression of NE-markers in surgically resected tumors. In a study by Berendsen et al. [l] patients with tumors having more than 50% positive NE-cells (MOC-I antibodies) had sig- nificant shorter survival than patients with NE-negative tumors after resection. Kibbelaar et al. ]2] analysed 308 surgically resected lung carcinomas of various histological subtypes, and NSCLC-tumors positive for Mab 123 C3 showed post- operative overall- and disease-free survival time significantly shorter than the 123 C3-negative tumors. The conclusion from these studies might be difficult to draw due to the retrospective character of the studies, relatively few patients included in the analyses and the different NE-markers used. More recently Sundaresan et al. [3] have published a preliminary report focus- ing on NE differentiation and survival in surgically treated cases of lung cancer and no correlation was found between NE- differentiation and survival, but the study suggested that NE- NSCLC was more highly metastatic than the non-NE-NSCLC.

Some chemotherapy studies have focused on the prognostic role of the presence of NE-markers. Graziano et al. [4] analysed 26 responders versus 26 non-responders and found that IO/26 (38%) responders were NE-positive compared to O/26 among the non-responders. Responders with two or more positive markers showed superior survival. In a study from our institu- tion [5] we analysed I I4 patients with inoperable adenocarcino- ma included in a prospective chemotherapy study and found a significantly higher response rate to chemotherapy in the NSE- positive group (44% vs. 17%). Although, we found a tendency to a longer survival for the NSE-group (median 262 days versus 159 days) there was no statistically significant. Van Zandwijk et al. [6] found a positive correlation between serum-NSE and response on chemotherapy in locally advanced or metastatic NSCLC, but no significant correlation to survival. Two preli- minary reports have recently been published: Carles et al. [7] examined 97 patients with NSCLC treated with chemotherapy. NSE was predictive for a better survival (median 11 months versus 7.4 months) compared to the NE-negative tumors, and in the study by Ruchdeschel et al. [8] including 237 resected NSCLC patients and 219 patients with extensive NSCLC or SCLC, NSE in patients with extensive disease was associated with an improved response to chemotherapy, but NE-markers had no influence on survival in resected patients.

From the studies in the literature it might be concluded that the presence of NE-markers are correlated to a higher response