Osteosarcoma in a Patient Receiving Long-Term TNF Inhibitor Therapy.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing malignancy. The use of immunosuppressive therapies and tumour necrosis factor (TNF) inhibitors in these patients may provide a further risk for the development of malignancy. We report the clinical and pathological findings of a high grade osteosarcoma in a patient with Crohns disease receiving TNF inhibitor therapy. In this case, a 32-year old female presented with a painful right knee after receiving maintenance adalimumab for Crohns disease for a period of six years. There is a substantial hypothetical link between TNF inhibitor regimens such as adalimumab and an increased risk of malignancy. TNF inhibitor therapy should be ceased and chemotherapy and surgery is an effective combined modality approach in these patients. The role of TNF inhibitors in patients after cancer diagnosis is uncertain and further research is required to assess efficacy and safety.

High levels of intracellular bombesin characterize human small-cell lung carcinoma.

"Small cells" or "oat cells" characterize a virulent form of lung cancer and share many biochemical properties with peptide-secreting neurones. The neuropeptide bombesin is present in all small-cell lines examined, but not in other lung cancer cell lines, suggesting that bombesinergic precursor cells in lung may give rise to this disease.

Specific chromosome defect associated with human small-cell lung cancer; deletion 3p(14-23).

A specific, acquired chromosomal abnormality (deletion 3p) has been found in at least one chromosome 3 in 100 percent of the metaphases in 12 of 12 cell lines cultured from human small-cell lung cancer tissue and in 2-day tumor culture specimens from three patients. Analysis of the shortest region of overlap shows the deletion to be 3p(14-23). This specific change was not seen in five of five lung cancer cell lines other than small-cell lung cancer or in two lymphoblastoid lines cultured from cells of small-cell lung cancer patients whose tumors had the 3p deletion.

Osteosarcoma and second malignant neoplasms: a case series.

BACKGROUND: The overall survival of patients with localised osteosarcoma has dramatically improved with the introduction of multidrug chemotherapeutic regimens into the treatment paradigm. However, despite optimal treatment, all-cause mortality remains higher among osteosarcoma survivors than in the general population. The development of second malignant neoplasms contributes to this higher mortality rate. CASE SERIES: We present three cases of patients definitively treated for osteosarcoma who subsequently developed a second malignant neoplasm. The first case describes a 17-year-old female with osteosarcoma of her right femur treated with surgical resection and perioperative chemotherapy. Ten years later, she was diagnosed with metastatic HER2-positive breast cancer. Genetic testing identified a germline TP53 mutation, confirming the presence of Li-Fraumeni syndrome. The second case details an 18-year-old male with osteosarcoma of his right humerus treated with definitive resection and perioperative chemotherapy. He was diagnosed with appendiceal adenocarcinoma after presenting with acute abdominal pain 17 years later. The third case reviewed is of a 36-year-old male with osteosarcoma of his right femur treated with definitive resection and adjuvant chemotherapy. A diagnosis of leiomyosarcoma was made 7 years later following surveillance imaging. DISCUSSION: The risk of second malignant neoplasms in osteosarcoma may relate to previous oncological treatment, an inherited cancer predisposition syndrome or a spontaneous new neoplasm. Although screening for a second malignancy is not routinely recommended for osteosarcoma survivors, a high degree of clinical suspicion should be maintained during surveillance.

Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells.

The antitumor activity of the antineoplastic agent, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), has previously been shown to require intracellular anabolism of the drug to a nicotinamide adenine dinucleotide (NAD) analog (2-beta-D-ribofuranosylthiazole-4-carboxamide adenine dinucleotide or "tiazofurin adenine dinucleotide"), which then acts as a potent inhibitor of the target enzyme inosine monophosphate (IMP) dehydrogenase. Inhibition of the latter enzyme in turn brings about a profound depletion of intracellular guanosine nucleotides essential for tumor cell growth and replication. In the present study, the cytotoxicity and metabolism of tiazofurin have been examined in six human lung cancer cell lines. At the pharmacologically attainable drug concentration of 100 microM, colony survival was less than 1.5% in three cell lines ("sensitive"), while survival in the remaining three was greater than 50% ("resistant"). The metabolism of tritiated tiazofurin was examined at concentrations ranging from 0.5 to 100 microM following both brief (6 h) and protracted (14 d) exposures. The sensitive lines accumulated concentrations of tiazofurin adenine dinucleotide that were approximately 10 times those achieved by the resistant lines at both time points. We also observed tendencies for the sensitive cell lines to exhibit: (a) higher specific activities of NAD pyrophosphorylase, the enzyme required for the synthesis of tiazofurin adenine dinucleotide, (b) significantly lower levels of a phosphodiesterase which degrades the latter dinucleotide, (c) greater inhibition of the target enzyme IMP dehydrogenase, and (d) greater depressions of guanosine nucleotide pools after drug treatment. By contrast, the basal levels of IMP dehydrogenase and purine nucleotides in these six lines did not correlate in any obvious way with their responsiveness or resistance. The accumulation and monophosphorylation of parent drug were also not prognostic variables. These studies thus suggest that the extent of accumulation of tiazofurin adenine dinucleotide, as regulated by its synthetic and degradative enzyme activities, is the single most predictive determinant of the responsiveness of cultured human lung tumor cells to tiazofurin.

DNA content analysis by flow cytometry and cytogenetic analysis in mycosis fungoides and Sézary syndrome.

Flow cytometric (FCM) analysis of DNA content was performed on 82 lymph node and peripheral blood specimens from 46 patients with mycosis fungoides and the Sézary syndrome. Overall, 32 of the 46 patients (70%) had aneuploidy detected by FCM. Aneuploidy was present in 63% of the patients at the time of diagnosis before systemic therapy. In these patients, aneuploidy was frequently detected in blood and lymph node specimens scored as negative by cytology and histology, suggesting that unsuspected extracutaneous dissemination is present in many patients at the time of diagnosis. Direct comparison with Giemsa-banded cytogenetic studies showed an excellent correlation of FCM results and cytogenetic chromosome number. However, FCM frequently detected a larger fraction of aneuploid cells, and mitogen-stimulation studies suggest this is the result of preferential stimulation of normal lymphocytes by phytohemagglutinin. Thus, mitogens with a preference for malignant T cells, such as staphylococcal protein A, should be used for cytogenetic analysis of malignant T-cell disorders. At diagnosis, some histologically positive specimens contained only diploid cells by FCM and cytogenetic analysis. These patients had a more indolent clinical course than patients with aneuploidy. Aneuploidy was detected by FCM as either wide G(1) or as discrete aneuploid peaks. The presence of aneuploidy at any time in the clinical course implied a poor prognosis. Discrete hyperdiploid peaks were associated with large cell histology, early relapse, and aggressive clinical course. The development of hyperdiploidy at relapse was documented in four patients and was associated with a transition to large cell histology and a poor prognosis. Similar studies may elucidate differences in natural history and mechanism for transition in histology in other lymphomas and solid tumors.

Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate.

We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.

myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course.

44 small cell lung cancer cell lines established from 227 patients were studied for myc family DNA amplification (c-myc, N-myc, and L-myc). Two of 19 lines (11%) established from untreated patients' tumors had DNA amplification (one N-myc and one L-myc), compared with 11 of 25 (5 c-myc, 3 N-myc, and 3 L-myc) cell lines (44%) established from relapsed patients' tumors (P = 0.04). The 19 patients who had tumor cell lines established before chemotherapy treatment survived a median of 14 wk compared with 48 wk for the 123 extensive stage patients who did not have cell lines established (P less than 0.001). Relapsed patients whose cell lines had c-myc DNA amplification survived a shorter period (median of 33 wk) than patients whose cell lines did not have c-myc amplification (median of 53 wk; P = 0.04). We conclude that myc family DNA amplification is more common in tumor cell lines established from treated than untreated patients' tumors, and c-myc amplification in treated patients' tumor cell lines is associated with shortened survival.

Changes in the phenotype of human small cell lung cancer cell lines after transfection and expression of the c-myc proto-oncogene.

Small cell lung cancer growing in cell culture possesses biologic properties that allow classification into two categories: classic and variant. Compared with classic small cell lung cancer cell lines, variant lines have altered large cell morphology, shorter doubling times, higher cloning efficiencies in soft agarose, and very low levels of L dopa decarboxylase production and bombesin-like immunoreactivity. C-myc is amplified and expressed in some small cell lung cancer cell lines and all c-myc amplified lines studied to date display the variant phenotype. To investigate if c-myc amplification and expression is responsible for the variant phenotype, a normal human c-myc gene was transfected into a cloned classic small cell lung cancer cell line not amplified for or expressing detectable c-myc messenger RNA (mRNA). Clones were isolated with one to six copies of c-myc stably integrated into DNA that expressed c-myc mRNA. In addition, one clone with an integrated neo gene but a deleted c-myc gene was isolated and in this case c-myc was not expressed. C-myc expression in transfected clones was associated with altered large cell morphology, a shorter doubling time, and increased cloning efficiency, but no difference in L dopa decarboxylase levels and bombesin-like immunoreactivity. We conclude increased c-myc expression observed here in transfected clones correlates with some of the phenotypic properties distinguishing c-myc amplified variants from unamplified classic small cell lung cancer lines.

Is chemotherapy always required for cancer in pregnancy? An observational study.

BACKGROUND: Cancer in pregnancy is relatively rare, but the incidence is increasing. Several studies show that cytotoxic agents are safe to use in pregnancy from the second trimester onwards. AIMS: This study assesses the maternal and foetal outcomes of cancers diagnosed during pregnancy. In particular, it focuses on a subset of women who elected to defer systemic chemotherapy until after delivery. This study examines if all cancers need to be treated during pregnancy or if, in certain cases, treatment can be safely deferred until after full-term delivery. METHODS: This is a retrospective observational study of women diagnosed with cancer during pregnancy in an Irish cancer centre over a 27-year period. All women diagnosed with cancer during pregnancy who were referred to the medical oncology department for consideration of chemotherapy were included in this study. Medical and pharmacy records were extensively reviewed. RESULTS: Twenty-five women were diagnosed with cancer in pregnancy and referred to medical oncology for consideration of systemic chemotherapy. Sixteen women (64%) commenced chemotherapy during pregnancy, seven women (28%) did not receive chemotherapy while pregnant, but commenced treatment immediately after delivery, and two (8%) did not receive any systemic chemotherapy at all. Of the seven women who commenced chemotherapy after delivery, six (85.7%) were diagnosed before 30/40 gestation. There were three cases of Hodgkin's lymphoma, two breast cancers and one ovarian cancer. After a median follow-up of 12 years, all six mothers remain disease-free. CONCLUSIONS: This study identified a select cohort of patients that did not receive chemotherapy during pregnancy. There were no adverse outcomes to mothers due to delayed treatment.

Suppression of malignancy in human lung cancer (A549/8) times mouse fibroblast (3T3-4E) somatic cell hybrids.

Interspecies hybrid cells were formed by the fusion of two parent cells: 1) the human lung cancer (bronchioloalveolar) line A549/8, which is not contact inhibited, rapidly produces tumors in athymic nude (nu/nu) mice, and forms colonies in agarose, and 2) the mouse fibroblast line 3T3-4E, which is contact inhibited, is nontumorgenic in nuce mice, and does not form colonies in agarose. These hybrid cells were tested 40-50 generations after fusion. The presence of 20 of the 23 different human chromosomes was tested by isoenzyme analysis, and examples of expression of each isoenzyme marker were found in at least some hybrid clones. All 14 independent hybrid clones tested were nontumorigenic in nude mice. Testing of hybrid clones for their ability to form colonies in agarose revealed two distinct phenotypes: agarose (clones forming colonies at 1-4% of the plated cells) and agarose (no colonies formed/10(5) cells tested). These phenotypes were discordant with all human isoenzymes tested. Malignant human lung cancer A549/8 times non-malignant mouse 3T3-4E cell hybrids were nontumorigenic in nude mice; thus malignancy of the bronchioloalveolar lung cancer behaved as a recessive trait. This nontumorigenicity was not accounted for by an absolute loss of the human chromosomes tested, but gene dosage may play a role. In contrast, the ability to clone in agarose was expressed in some hybrids (and thus behaved as a dominant trait); at present, agarose clonability cannot be related to specific human chromosomes.

Inhibition of DNA synthesis by a small-cell lung carcinoma-derived protein.

A tumor-derived factor that inhibits cellular DNA synthesis was identified. The factor was extractable from a small-cell lung carcinoma cell line grown in either chemically defined medium or nu/nu mice and inhibited tritiated thymidine ([3H]dThd) incorporation by tumor cell lines of autologous, allogeneic, and xenogeneic origins. The viability of nonproliferating cells from normal tissue was not affected. Tumor extract inhibitory activity was trypsin labile but was resistant to other proteases, neuraminidase, lipase, DNase, RNase, glucosidase, extremes of pH-temperature, and reducing conditions. Inhibitory activity was reversibly bound to helix pomatia lectin but not to lentil, wheat germ, or concanavalin A lectins. Purification by size-exclusion high-performance liquid chromatography yielded a bioactive unimodal 12-kilodalton (kd) peak. The bioactive 12-kd moiety could be eluted from sodium dodecyl sulfate-polyacrylamide gels. Redosing of populations of the T-lymphoblastoid cell line CEM achieved an early (24 hr) sustained depression of pulse [3H]dThd incorporation and ultimately led to decreased population density of factor-treated populations. DNA histogram analysis demonstrated no change in cell cycle phase distribution after factor treatment. 5-Bromo-2'-deoxyuridine (BrdUrd) vs. propidium iodide with the two-parameter Fluorescence-Activated Cell Sorter analysis showed relative inhibition of non-S-phase BrdUrd uptake at 24 hours. A cell-free DNA polymerase assay demonstrated significant inhibition of non-alpha-polymerase-associated DNA synthesis in factor-treated cells. These studies suggest that this tumor-derived inhibitor of DNA synthesis represents a class of cellular products involved in the autoregulation of growth by regulation of DNA synthetic activity.

Heterogeneity in the radiation survival curves and biochemical properties of human lung cancer cell lines.

Human lung cancers of distinct histology exhibit different responses to radiation therapy in vivo. For examination of the basis of this phenomenon, the radiation survival curves and levels of relevant enzymes were determined in 16 lung cancer cell lines derived from tumors of different histology. These included lines from 5 adenocarcinomas, 7 small cell tumors, 3 variant small cell tumors, and 1 large cell tumor. These findings were compared to those obtained with the use of a normal skin fibroblast cell line. Whether cloned in liquid culture or soft agarose, cell lines had similar radiation survival curves. These curves were consistent with the apparent in vivo radiation responsiveness of the tumors. Although considerable heterogeneity in radiation survival curves was observed among the cell lines, cells from large cell lines and small variant lines had pronounced shoulders and extrapolation numbers (n) from 5.6 to 14. In contrast, cells from small cell lines and adenocarcinoma cell lines were more "sensitive" (-n values of 1-3.3). In these cell lines, levels of DNA polymerase beta, glutathione (GSH), GSH transferase, GSH reductase (NAD(P)H), gamma-glutamyltransferase did not correlate with radiation parameters of sensitivity. DNA polymerase beta and GSH levels were, however, higher than those in a line of normal skin fibroblasts. These cell lines may be useful in identifying the basis of the variable responsiveness of human lung cancer cells to ionizing radiation.

Influence of histologic subtype of small cell carcinoma of the lung on clinical presentation, response to therapy, and survival.

Patients with small cell carcinoma of the lung (SCCL) were histologically subtyped according to the Working Party for Therapy of Lung Cancer classification and were treated with combination chemotherapy. Of the 103 patients studied, 54 had the lymphocyte-like (oat cell) subtype, 41 had the intermediate cell subtype, and 8 had a mixture of the two. No significant difference in initial performance status, extent of disease, chemotherapeutic response rate, or survival (median, 10.2 mo) was noted among the histologic subtypes. When the histologic subtype of the primary biopsy tissue was compared with the subtype of other pathology specimens from the same patient, concordance of subtype was present in 74% of the patients. In the remaining 26%, two or three histologic subtypes were present. This study demonstrates no clinically significant differences among the various histologic subtypes of SCCL in patients extensively staged and treated with aggressive cytotoxic therapy. Because of this and because concurrent biopsy tissues from multiple sites in the same patient may vary in subtype, we conclude that prognostic or therapeutic decisions should not be based on SCCL subtype.

Continuous culture and soft agarose cloning of multiple human breast carcinoma cell lines in serum-free medium.

We tested the ability of a serum-free medium containing insulin, transferrin, 17 beta-estradiol, dexamethasone, triiodothyronine, prostaglandin F2 alpha, and fibronectin (HBCA medium) to support the continuous growth and passage of five human breast carcinoma cell lines on a collagen matrix. Doubling times of the cell lines (20 to 44 hr) were similar in HBCA and serum-supplemented media. The gross morphology of the cell lines was not altered in the serum-free medium. Insulin, transferrin, and the collagen matrix were the most essential factors required for optimal growth of the cell lines. Estradiol appeared to stimulate the growth of cell lines, both with and without estrogen receptors. HBCA medium supplemented with low concentrations of bovine serum albumin, Fraction V (0.5%, v/v), supported the clonal growth of three cell lines in soft agarose with colony-forming efficiencies superior to that observed with standard serum-supplemented medium. Deleting estradiol from HBCA medium reduced the colony-forming efficiency of the three cell lines. HBCA medium may be useful in studying hormonal regulation and improving the in vitro growth of human breast cancer.

In vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants.

The in vitro response to radiation and chemotherapeutic drugs of cell lines established from 7 patients with small cell (SC) lung cancer were tested using a soft agarose clonogenic assay. Five cell lines retained the typical morphological and biochemical amine precursor uptake decarboxylation characteristics of SC, while two cell lines had undergone "transformation" to large cell (LC) morphological variants with loss of amine precursor uptake decarboxylation cell characteristics of SC. The radiation survival curves for the SC lines were characterized by D0 values ranging from 51 to 140 rads and extrapolation values (n) ranging from 1.0 to 3.3. While the D0 values of the radiation survival curves of the LC variants were similar (91 and 80 rads), the extrapolation values were 5.6 and 11.1 In vitro chemosensitivity testing of the cell lines revealed an excellent correlation between prior treatment status of the patient and in vitro sensitivity or resistance. No correlation was observed between in vitro chemosensitivity and radiation response. These data suggest that transformation of SC to LC with loss of amine precursor uptake and decarboxylation characteristics is associated with a marked increase in radiation resistance (n) in vitro. The observation of a 2- to 5-fold increase in survival of the LC compared to the SC lines following 200 rads suggests that the use of larger daily radiation fractions and/or radiation-sensitizing drugs might lead to a significantly greater clinical response in patients with LC morphology. This clinical approach may have a major impact on patient response and survival.

Positive correlation between histological tumor involvement and generation of tumor cell colonies in agarose in specimens taken directly from patients with small-cell carcinoma of the lung.

Twenty-seven specimens for in vitro agarose clonogenicity testing were obtained from 25 patients with small-cell carcinoma of the lung (SCCL). The specimens were obtained from bone marrows, pleural effusions, lymph nodes, and liver biopsies. Colony formation was seen in 14 of 15 specimens that were histologically involved with SCCL, but no colony growth was seen in the 12 patient specimens without histocytopathological evidence of SCCL, including seven bone marrow specimens. Cytological examination of the agarose colonies confirmed their SCCL origin. Colonies reached sizes of 50 to 1000 cells in 7 to 10 days, indicating an in vitro doubling time of less than 24 hr, remarkably shorter than the population doubling times measured in patients. None of the 100 clones picked from these specimens demonstrated the ability to continuously replicate in vitro. These results show an excellent correlation between agarose colony formation and histological tumor involvement and a more rapid in vitro doubling time than that seen in vivo and demonstrate that standard tissue culture conditions do not allow demonstration of a self-renewing stem cell in fresh tumor specimens of SCCL.

Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties.

We have described the establishment and biochemical characterization of 50 small cell lung carcinoma (SCLC) cell lines. Further analysis of these data, combined with studies of morphology and growth characteristics, indicates that 35 (70%) of the lines retained typical morphology (SCLC, intermediate subtype), growth characteristics (growth as tightly packed floating cellular aggregates, long doubling times and low colony-forming efficiencies), and biochemical profile (presence of L-dopa decarboxylase, bombesin-like immunoreactivity, neuron-specific enolase, and high concentrations of brain isoenzyme of creatine kinase). They are referred to as classic SCLC lines. The remaining 15 (30%) lines had discordant expression of the biochemical markers; they retained high concentrations of brain isozyme of creatine kinase, but had significantly lower concentrations of neuron-specific enolase and lacked L-dopa decarboxylase and bombesin-like immunoreactivity. These cell lines are called variants. SCLC variant lines could further be divided into (a) biochemical variant lines having variant biochemical profile but retaining typical SCLC morphology and growth characteristics; and (b) morphological variant (SCLC-MV) lines having variant biochemical profile, altered morphology (features of large cell undifferentiated carcinoma) and altered growth characteristics (growth as loosely attached floating aggregates, relatively short doubling times and cloning efficiencies). Fifty-five clones derived from the three SCLC subclasses retained their parental phenotypes. In SCLC-MV lines there was a near constant relationship between variant morphology, altered growth characteristics and amplification of the c-myc oncogene; classic SCLC and biochemical variant SCLC lines were not amplified. Variant morphologies frequently are present in SCLC tumors at autopsy, and most SCLC-MV lines reflect changes that had occurred in the tumors from which they were derived. Because SCLC-MV tumors behave more virulently in the patient and are radioresistant in vitro, these findings are of considerable biological and clinical interest.

Selective stimulation of small cell lung cancer clonal growth by bombesin and gastrin-releasing peptide.

Human small cell lung cancers (SCLC) produce and secrete the regulatory peptide bombesin (BN) or its mammalian counterpart gastrin-releasing peptide (GRP). In addition, several SCLC tumor lines have been shown to express high affinity receptors for BN/GRP. On the basis of these findings, we investigated the effect of exogenously added BN and GRP on the soft agarose colony growth of a panel of human cell lines. In serum-free defined medium, colony formation of 9 of 10 SCLC cell lines was stimulated up to 150-fold by BN or GRP, with peak colony stimulation observed at 50 nM BN. In contrast, no stimulatory effect of BN was observed on nine non-SCLC cell lines. Although no stimulation of colony growth by BN was seen in serum-supplemented medium, addition of BN to the serum-free medium increased cloning efficiency to that achieved by serum in most of the SCLC cell lines. GRP 1-27, the active mammalian analogue of Bn, stimulated colony growth of SCLC cells similar to the manner of BN, while the physiologically inactive BN analogue, des-Leu (13)-Met (14)-BN, had no effect on colony growth. No correlation was observed in SCLC cell lines between the response of these cells to exogenous BN and the amount of cellular BN/GRP produced or the presence of BN receptors. These data suggest that BN/GRP may in some instances function as an autocrine growth factor for SCLC and indicate new ways for modulating SCLC growth in patients with this tumor.

In vitro growth inhibition of human small cell lung cancer by physalaemin.

Production and secretion of neuroendocrine peptides by small cell lung cancer (SCLC) has been detected in the past years. Most recently the role of bombesin as an autocrine/paracrine growth modifier has been demonstrated. We used the soft agarose clonogenic assay to evaluate the influence of other neuroendocrine peptides on the in vitro proliferation of SCLC cell lines. Neuroendocrine peptides tested were adrenocorticotropic hormone, arginine vasopressin, calcitonin, glucagon, kassinin, neurotensin, physalaemin, somatostatin, and substance P. Experiments were carried out in serum-free and serum-supplemented media with and without serum-free incubation periods. Our results indicated that the amphibian undecapeptide physalaemin inhibits the clonal and mass culture growth of SCLC cell lines at picomolar concentrations. All other neuroendocrine peptides failed to influence SCLC growth in the test systems used. These results suggest a growth regulating effect of physalaemin and a potential new form of neuroendocrine peptide therapy for SCLC.