Lung Carcinomas In Mice Research Articles

Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

Inhibition of tumor growth by U0126 is associated with induction of interferon‐γ production

Several MEK1/2 inhibitors have been in clinical trial evaluation for cancer treatment. Interferon-γ (IFN-γ) is a cytokine with multiple biological functions including antitumor activity. Expression of IFN-γ can be induced by liver X receptor (LXR), a ligand-activated transcription factor. However, it remains unknown if the anti-cancer action of MEK1/2 inhibitors is completed, at least in part, by activating IFN-γ expression. In this study, we determined that U0126, a MEK1/2 inhibitor, increased tumor-free and survival rates and decreased growth of inoculated Lewis lung carcinomas in wild type mice. However, the protective effects were substantially attenuated in IFN-γ deficient (IFN-γ-/-) mice. At cellular and molecular levels, MEK1/2 inhibitors increased IFN-γ protein and mRNA expression and activated natural IFN-γ promoter but not the IFN-γ promoters with mutations of the LXR responsive elements (LXREs). MEK1/2 inhibitors also enhanced formation of the LXRE-nuclear protein complexes by inducing LXR expression and nuclear translocation. Similarly, MEK1/2 siRNA inhibited phosphorylation of ERK1/2 by MEK1/2 while activated IFN-γ expression. In contrast, inhibition of LXR expression by siRNA blocked MEK1/2 inhibitors-induced IFN-γ expression. U0126 also inhibited chemicals-induced pulmonary carcinomas, which was associated with increased IFN-γ expression in the lung. Taken together, our study suggests that MEK1/2 inhibitors induce IFN-γ production in an LXR-dependent manner and the induction of IFN-γ expression can partially contribute to the anti-tumorigenic properties of U0126.

Inhalation carcinogenicity of dichloromethane in rats and mice

The carcinogenicity of inhaled dichloromethane (DCM) was examined by exposing groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of both sexes to 0, 1000, 2000, or 4000 ppm (w/w) DCM-containing aerosol for 2 years. Inhalation of DCM resulted in increased incidences of subcutis fibromas, mammary gland fibroadenoma, and peritoneum mesotheliomas in male rats; mammary gland fibroadenomas in female rats; and bronchiolar–alveolar adenomas and carcinomas in the lung and hepatocellular adenomas and carcinomas in male and female mice. These results clearly indicate that inhaled DCM is carcinogenic in F344/DuCrj (SPF) rats and Crj: BDF1 (SPF) mice.

Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer

In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis. Previously, a weak competitive inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found to reduce the glucose metabolism and proliferation of cancer cells. We have synthesized 73 derivatives of 3PO and screened each compound for activity against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), was selected for further preclinical evaluation of its pharmacokinetic, antimetabolic, and antineoplastic properties in vitro and in vivo. We found that PFK15 causes a rapid induction of apoptosis in transformed cells, has adequate pharmacokinetic properties, suppresses the glucose uptake and growth of Lewis lung carcinomas in syngeneic mice, and yields antitumor effects in three human xenograft models of cancer in athymic mice that are comparable to U.S. Food and Drug Administration-approved chemotherapeutic agents. As a result of this study, a synthetic derivative and formulation of PFK15 has undergone investigational new drug (IND)-enabling toxicology and safety studies. A phase I clinical trial of its efficacy in advanced cancer patients will initiate in 2013 and we anticipate that this new class of antimetabolic agents will yield acceptable therapeutic indices and prove to be synergistic with agents that disrupt neoplastic signaling.

Cardiac hormones eliminate some human squamous lung carcinomas in athymic mice

Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, have anticancer effects in vitro. These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 0.3 nM kg(-1) body weight in athymic mice bearing human squamous cell carcinomas. Vessel dilator, atrial natriuretic peptide and kaliuretic peptide each eliminated one in six (17%) of the human squamous cell lung carcinomas. Long-acting natriuretic peptide, although it did not eliminate any of the human squamous cell lung carcinomas did decrease the volume of one carcinoma to only 2% (P < 0.0001) of the untreated carcinomas. The squamous cell lung carcinomas that were not eliminated, with the exception of the one LANP-treated tumour that decreased to only 2% of the volume of the untreated cancers, grew rapidly but their growth velocity compared to controls decreased by 76%, 40%, 38% and 25% in the vessel dilator, atrial natriuretic peptide, kaliuretic peptide and long-acting natriuretic peptide groups respectively (P < 0.05). Three of four cardiac hormones synthesized by the atrial natriuretic peptide gene can eliminate human squamous cell lung carcinomas in athymic mice when treated subcutaneously for 4 weeks. The 4th cardiac hormone, i.e. long-acting natriuretic peptide, decreased the volume of one squamous cell lung carcinoma to 2% of that of untreated animals, suggesting that it, too, has beneficial effects on squamous cell lung cancers.

Abstract A92: Chemoprevention of small cell lung carcinomas in mice by the retinoid X receptor agonist bexarotene

Abstract In the present study, we examined the effect of bexarotene (Targretin) and budesonide in chemoprevention of small cell lung carcinoma (mSCLC) using a lung specific knockout model of Rb1 and p53. Upon treatment with bexarotene, tumor incidence, number, and load were significantly reduced (p &amp;lt; 0.05). Budesonide treatment trended to inhibition, but the effect was not statistically significant (p &amp;gt; 0.05). Immunohistochemical staining indicated that bexarotene treatment decreased cell proliferation and increased apoptosis in tumors. The Rb1/p53 gene targeted mouse appears to be a valuable model for chemopreventive studies on human small cell lung cancer (hSCLC). Our results indicate that the retinoid X receptor (RXR) agonist bexarotene may be a potent chemopreventive agent in this cancer type. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A92.

Cardiac and kidney hormones cure up to 86% of human small‐cell lung cancers in mice

Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, and the kidney hormone urodilatin have anticancer effects in vitro. These cardiac hormones and urodilatin were infused subcutaneously for 28 days with weekly fresh hormones since they lose biological effects at body temperature for more than a week at 0.3 nm kg(-1) body weight in athymic mice bearing human small-cell lung carcinomas. Long acting natriuretic peptide, vessel dilator, kaliuretic peptide, atrial natriuretic peptide and urodilatin eliminated 86%, 71%, 57%, 43% (P < 0.001 for the cardiac hormones) and 25% (P < 0.05; urodilatin) of the human small-cell lung carcinomas. The treated small-cell lung carcinomas that were not cured grew rapidly, similar to the untreated controls, whose volume was 7 fold larger in 1 week, 18-fold increased in 2 weeks, 39-fold increased in 3 weeks, 63-fold increased in 1 month and 97-fold increased in volume in 6 weeks. One vessel dilator treated small-cell lung carcinoma animal developed a large tumour (8428 mm3 volume) on treatment and this tumour was eliminated with utilizing atrial natriuretic peptide and then long acting natriuretic peptide sequentially. Four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas in athymic mice. Urodilatin can also eliminate small-cell lung carcinomas but at a lower cure rate of 25%. Unresponsive lesions can be eliminated by utilizing different hormones synthesized by the atrial natriuretic peptide gene in a sequential manner.

Rac GTPases Modulate Migration of Hematopoietic Progenitor Cells in an SDF-1α Dependent Manner in a Tumor Model.

Rac GTPases have been shown to regulate marrow retention, engraftment, and mobilization of hematopoietic stem and progenitor cells. Recruitment of bone-marrow derived progenitor cells (BMPCs) to tumor stroma has been found to be critical for tumor development. To investigate to what extent BMPC-dependent tumor growth depends on small GTPases of the Rac family, we established subcutaneous Lewis Lung Carcinomas (LLCs) in mice with deleted Rac2 alleles (Rac2−/−), or with additionally deleted Rac1 alleles in hematopoietic cells generated by polydIdC induction of Mx-Cre in Rac1fl/fl; Rac2−/− mice (Rac1delta/delta; Rac2−/−). We found that compared with wild-type mice, tumor growth was equal or accelerated by up to 2.5 days in Rac2−/−mice, whereas tumor growth was reduced in Rac1delta/delta; Rac2−/− mice. Flow cytometric analysis of tumors in chimeric mice generated by transplanting Rac deficient bone marrow cells (CD45.2) into CD45.1 hosts showed that >95% of CD45+ cells contained within tumors were bone marrow-derived, including lin− Sca1+ Hematopoietic Progenitor Cells (HPCs) which were found highly enriched in tumors. Histological examination of tumor sections, including quantitative morphometric analysis, revealed that tumor microvessel density was similar in wild type and Rac deficient mice. In murine blood, tumor inoculation resulted in increased numbers of lin−Sca1+ HPCs, myeloid colony forming cells and myeloid mononuclear cells compared to non-tumor bearing mice. These numbers were similar in Rac2−/− and wild type tumor-bearing mice, but were >2-fold increased in Rac1delta/delta; Rac2−/−mice. Since LLC tumors produced significant amounts of SDF-1α (120 pg/ml) and since VLA-4/VCAM-1 and SDF-1α/CXCR4 have been shown to be major mediators of HPC egress and retention in tumor stroma (Grunewald et al, Cell 124:175, 2006; Jin et al. JCI 116:652, 2006), we analyzed the adhesion and migration response of HPCs from tumor-bearing Rac2−/− and Rac1delta/delta; Rac2−/− deleted mice (i) in laminar flow chambers on VCAM-1 with and without co-immobilized SDF-1α and (ii) upon re-injection into tumor-bearing mice in vivo. In the absence of SDF-1α, both Rac2−/− and Rac1delta/delta; Rac2−/− HPCs dispayed decreased adhesion to VCAM-1 at caculated shear stresses between 0.35 and 15 dynes/cm2. In contrast, Rac2−/− HPCs displayed a highly conserved ability to adhere to VCAM-1 when SDF-1α was co-immobilized, whereas Rac1delta/delta; Rac2−/− HPCs showed a 2–3-fold decrease in adhesion under these conditions. Intravenous injection of PKH dye-labelled lin− bone marrow cells into LLC tumor-bearing wild type hosts followed by flow cytometric and histological analysis 24 h later confirmed the retained ability of Rac2−/− HPCs to home to tumors. Our data explain the observed undiminished and even increased tumor growth in Rac2−/− mice by the grossly maintained response of Rac2−/− HPCs to VCAM-1 plus SDF-1a, whereas the impaired response to SDF-1α-induced adhesion on VCAM-1 in Rac1delta/delta; Rac2−/− mice is associated with inferior recruitment and/or retention in tumors and impaired tumor growth. Thus, interference with Rac1 and 2 signalling may provide a means to influence tumor development.

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

Cellular actions of angiogenesis inhibitors on blood vessels

Cellular actions of angiogenesis inhibitors on blood vessels

Parathyroid hormone‐related protein varies with sex and androgen status in nonsmall cell lung cancer

In nonsmall cell lung cancer, tumor parathyroid hormone-related protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex-dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells. Tumor PTHrP content was measured by immunoassay, and tumor burden was assessed with multiple measures in BEN squamous cell orthotopic lung carcinomas in athymic mice. In addition, lung adenocarcinoma PTHrP messenger RNA (mRNA) values determined by microarray analyses were compared between men and women. Cultured lung cancer cells were assayed for PTHrP after treatment with estradiol or R1881, a synthetic androgen. Lung carcinomas contained approximately 3 times more PTHrP in female mice than in male mice. Similarly, levels of PTHrP mRNA were significantly greater in adenocarcinomas from patients who were women than from patients who were men. Male mice had greater tumor burden than female mice. Androgen treatment reduced PTHrP in 3 lung cancer lines. Estradiol had no effect. Testosterone treatment also reduced lung carcinoma PTHrP in female mice. Lung carcinomas in females expressed more PTHrP than in males possibly because of negative regulation by androgens in males. Female mice with higher tumor PTHrP content had significantly less tumor burden than male mice, supporting the hypothesis that PTHrP inhibits tumor growth.

Rapid vascular regrowth in tumors after reversal of VEGF inhibition

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.

Potent anti-metastatic activity of combretastatin-A4

The requirement for tumour vascularisation to permit the expansion of solid tumours beyond a threshold size of approximately 1 mm diameter has focussed attention on anti-vascular and anti-angiogenic agents for cancer therapy. Combretastatin-A4 (cis CA-4P) is a tubulin-binding agent that is cytotoxic for proliferating endothelial cells in vitro and causes anti-vascular effects in the established tumour vessels of some primary tumours. Preliminary data from Phase I clinical trials indicate that cis CA-4 may also be effective in targeting the vasculature of human tumours. As metastatic disease is the principal cause of mortality in cancer, we have investigated the effects of cis CA-4 on metastatic development using an in vivo model. We show that bolus or continuous administration of cis CA-4P results in potent inhibition of metastases derived from ectopic primary Lewis lung carcinomas in mice whereas the trans CA-4 isomer is without effect. These data further characterise the activity of CA-4 in vivo and suggest that the drug should be evaluated clinically as an anti-metastatic agent.

Tumor-promoting activities of hydroquinone and 1,1-dimethylhydrazine after initiation of newborn mice with 1-methyl-1-nitrosourea

To clarify the suitability of a newborn-mouse carcinogenesis assay to detect tumor-promoting activities of carcinogens, the non-genotoxic hydroquinone (HQ) and genotoxic 1,1-dimethylhydrazine (UDMH) were administered to mice during the promotion stage after treatment with 1-methyl-1-nitrosourea (MNU) (20 mg/kg body wt, single intraperitoneal injection) at day 9 after birth. Initiated males and females thus received either HQ at 0.8% in basal diet, or UDMH, at 20 mg/kg body wt once weekly by subcutaneous injection, from day 14 until the end of the experiment at 30 weeks of age. Uninitiated newborn mice, given an injection of the vehicle (0.01 M citrate buffer (pH 5.5), 20 mg/kg body wt), also received HQ or UDMH in the same way. Histopathologically, focal proliferative lesions were found in the livers of male mice and in the lungs of both male and female mice in the MNU-treated groups. HQ significantly increased the incidence and multiplicity of altered hepatocellular foci, the combined incidence of hepatocellular adenomas and carcinomas in males and the incidence and multiplicity of lung adenomas and the combined incidence of lung adenomas and carcinomas in female mice. In addition, four out of eleven MNU+HQ-treated male mice developed lung carcinomas, showing a significant elevation in multiplicity. UDMH also exhibited a tendency to increase the incidence and multiplicity of lung adenomas in female mice. Thus tumor-promoting effects of HQ or UDMH were apparently exerted in the target organs and the MNU-initiated two-stage newborn-mouse carcinogenesis assay may be useful for detection of genotoxic or non-genotoxic carcinogenicity.

Superior therapeutic efficacy of N- l-leucyl-doxorubicin versus doxorubicin in human melanoma xenografts correlates with higher tumour concentrations of free drug

N- l-leucyl-doxorubicin (Leu-DOX), a prodrug of doxorubicin (DOX), has previously shown antitumour activity against human ovarian, breast and lung carcinomas in nude mice. In the present study, the efficacy of Leu-DOX was compared with free DOX in inhibiting the growth of four DOX-sensitive and -resistant malignant melanoma xenografts. In an attempt to elucidate mechanisms underlying any differential effect, a sensitive high-performance liquid chromatography (HPLC) method was established for measuring plasma and tumour concentrations of the two drugs and their main metabolites. Leu-DOX was more effective than free DOX in inhibiting xenograft growth. At equitoxic intravenous doses of Leu-DOX (28 mg/kg) and DOX (8 mg/kg) administered to tumour-bearing nude mice, comparable levels of DOX were found in plasma, whereas differences were seen in tumour tissue concentrations. Thus, in animals carrying highly sensitive (LOX) and resistant (THX) melanomas, higher tumour concentrations of free DOX were observed in the Leu-DOX treated group from 24 up to 240 h after drug injection. Notably, the difference in drug-induced tumour growth inhibition correlated with differences in tumour exposure to free DOX, assessed as area under the curve (AUC) calculated over the first 48 h. In conclusion, the results confirm the prodrug nature of Leu-DOX and provide a possible explanation for its increased antitumour efficacy.

Coexpression of cyclin D1 and retinoblastoma gene product (pRb) in human squamous cell lung carcinomas is associated with increased tumor take rate in nude mice

Samples from 72 squamous cell lung carcinomas were analyzed immunohistochemically for the expression of cyclin D1 and pRb. Expression of cyclin D1 was found in 61% and expression of pRb in 39% of the cases. The take rate of human squamous cell lung carcinomas in nude mice was significantly different according to the expression of cyclin D1 and expression of pRb in primary human tumors [cyclin D1-negative (32%) vs. cyclin D1-positive (59%); P=0.026; pRb-negative (34%) vs. pRb-positive (71%); P=0.002]. The take rate was improved by coexpression of both proteins [both proteins negative/both proteins positive: 12% vs. 80% (P=0.00005)]. An association of the take rate and clinical parameters (age, extent of tumors, lymph node involvement, stage) could not be observed. Coexpression of cyclin D1 and pRb is also a prognostic factor for the patients' survival.

Effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice: Pinski J, Schally AV, Halmos G, Szepeshazi K, Groot K, O'Byme K et al. VA Medical Center, 1601 Perdido Street, New Orleans, LA 70146. Br J Cancer 1994;70:886–892

Effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice: Pinski J, Schally AV, Halmos G, Szepeshazi K, Groot K, O'Byme K et al. VA Medical Center, 1601 Perdido Street, New Orleans, LA 70146. Br J Cancer 1994;70:886–892

Effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice

We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.

Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations : Volm M, Effert T, Mattern J. Deutsches Krebsforschungszentr, Im Neuenheimer Feld 280 W-6900 Heidelberg. Anticancer Res 1992;12:11–20

The expression of the protooncogene encoded proteins (c-erbB1, c-erb B2, c-myc, c-fos) and the suppressor gene product p53 was analyzed in 81 human squamous cell carcinomas of the lung and correlated with clinical parameters of the patients (patient survival, presence of metastases and tumor stage) and with biological characteristics of the tumors (tumor growth in nude mice, DNA-ploidy, proliferative activity, drug-resistance and P-glycoprotein or gluathione S-transferase expression). By means of immunohistochemistry, expression of c-erbB1 oncoprotein (EGF-receptor) was detected in 79% of the tumors, c-erbB2 (c-neu) proteins in 35%, c-myc proteins in 48%, c-fos proteins in 41%, and p53 in 43% of the tumors. Patients with c-erbB1 positive tumors had a poor prognosis (p = 0.021). In addition, these tumors were more frequently drug resistant (p = 0.0067). A significant correlation between the growth of the squamous lung carcinomas in nude mice and c-fos oncoprotein expression was demonstrated (p = 0.017). Therefore, EGF-receptor and c-fos products may serve as prognostic factors for the aggressiveness of squamous cell carcinomas of the lung and for the response of these tumors to chemotherapy. No significant correlation was found between the expression of the c-erbB1 or c-fos gene products and stage, metastasis and DNA-ploidy. In contrast to these results, no relationship was found between c-neu or c-myc gene products expression and any of the clinical or biological parameters examined. Aneuploid squamous cell carcinomas of the lung expressed p53 more frequently than diploid tumors (p = 0.027). However, there was no significant difference between p53 expression and stage, survival of patients, metastasis, growth of the tumors in nude mice, proliferative activity and drug-resistance of the tumors.

Production of lung carcinomas in C57BL mice exposed to a cigarette smoke and air mixture.

Production of lung carcinomas in C57BL mice exposed to a cigarette smoke and air mixture.