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paracrine insulin-like growth factor I-controlled proliferative loop on human lung cancer cell lines
316
Abstracts/Lung
Suramia interferes with auto/paracrine insulin-like growth factor coatmlled pmliferative loop 011 human lung cancer cell lines
Cancer I-
Favoni RE, Ravera F, Pirani P, Ardizmni A, Noonan D, Cupis de A. Depf.of Experimental Phormocolo~, Inst.Naz. per la Ricerca sul Concro, Vt& BenedettoXVlO, 16132 Gmova. Eur J Pharmacol 1994;264:199-206. Human non-small cell lung cancer (N-SCLC), a cmnmon malignancy generally unmanageable by conventional cytotoxic chemotherapy. represents a major world health burden. Suramin, a polyanionic drug which appears to interfere with growth-factor/receptor interaction, has recently been shown to be cytostatic for small cell lung cancer cellp; it may also be effective for NSCLC. As insulin-like growth factor I (IGF-I) is a known progression agent for N-SCLC, we have examined the effects of suramin on the ‘IGF-I system’ in a panel of human N-SCLC cell lines. Calorimetric and thymidinc incorporation assays were used to assess cell chemosensitivity whereas a rsdiwcceptor assay was employed to evaluate IGF-I/receptor binding. Suramin reversibly reduced, in a concentration- and time-dependent manner, the growth of each N-SCLC cell line examined either cultured in serumeontaining or serum-free medium. Furthemmre, suramin caused a concmtration-related inhibition of labeled IGF-I peptidc specific binding on all cell lines studied. Suramin caused a significant reduction in the B(max) values with only weak variations in the affinity constants (K(d)). WC hypothesize that suramin intcrfercmx with IGF-I mitogenic activity is a pathway by which this drug produces its effect in vitro. These data indicate further shrdies on the mechanism of action and pharmacology of suramin in viva *re warranted.
Wall PJ, Rozmgwt E. Imperial Cancer Research Fund, Lincoln i Inn Fields, London FVC2A 3PX Pmc Natl Acad Sci USA 1988,8S:l859-63. In the search for a mora potent bomb&n antagonist, we found [DArg’S Phc’,D-Trp’~,Lcucu”]substanstancc P to be effective in mouse tibroblasts and to inhibit the gmwth of small cell lung cancer, a tumor that secretes bombesin-like peptides that may act as autocrinc growth factors. In murinc Swiss 3T3 cells, ID-Afg’.DPhdPTrp’“~u”]substsncc P proved to be a bomb&n antagonist as judged by the following criteria: (i) inhibition of DNA synthesis induced by gasttinreleasing peptidc and other bombesin-like peptides; (ii) inhibition of ‘“I-laboled gastrin-releasing pcptide binding to the bombesin/gastrin-releasing peptidc receptor; (iii) reduction in cross-linking of the M 75,000-85,000 protein putatively a component of the bambesin/gastrin-releasing peptidc receptor, (iv) blocking of early c&dar events that precede mitogencsis-calcium mobilization and inhibition of cpidermal growth factor binding. [D-Arg’.D-Phc’,DTrp”Leu”]substancc P was 5-fold more potent than the antagonist PArg’PRo’,D-Trp~9,Leu”]substance l? ~~‘PPh~PTrp~qLcu”]substancc P also inhibits mitogenesis induced by vwpressin but not that induced by a variety of other mitogens. Both antagonists reversibly inhibited the growth of small cell lung cancer in vitro in a concentration-dependent manner. Pcptide antagonists could, therefore, have far-reaching therapeutic implications.
Late phase II clinical study of KW-2307 in previously untreated patients witb non-small cell lung cancer Furuse K. Kinuwaki E, Motomiya M, Nishiwaki H, Hascgawa K, Kobaysshi K et al. Department of Inferno/Medicine. National Kinki Central Hospital, Osaka. Jpn J Cancer Chemother 1994;21:1941-7. A late Phase II clinical study of KW-2307, a new vinca alkaloid derivative, in previously untreated patients with non-small cell lung cancer was jointly carried out in 26 medical instihltions. Of 80 enrolled cases, 75 casts were eligible, and PR was attained in 23 cases (30.7%). The main advnsc effect of this drug, leukopenia (ncutmpenia), was observed in 62.7% (83.3% ) of Grade 3 and 4 cases. but they recovered rapidly. In addition to decreased hemoglobin in 67% (Grade 3 in 5.7%) of the cases, adverse effects included slight disorder of hepatic function, anorexia, nausea and vomiting. fever, general fatigue, phlebitis, paresthesia and interstitial pneumonia. Peripheral neuropathy such as paresthesia occurred rarely and was slight, if any.
I2 (1995)
265-329
Bnmcbial arterial bemodynamics after tboracic irradiation therapy in lung cancer patients Nambu Y, Tamamura H, Ohguchi M, Mauri M, Kobayashi Y, Ysmanouchi K et al. Division ofRespiratmyDi.wse, Deportment offntanalMedicine, Karwza~~ Medical Universily, D&g& I-I. Uchinoda. Kahoku-gun, Ishikawa 920-02. Jpn J Thorac LXs 1994,32:644-9. WC evaluated bronchial arterial hemodynamics at?er thoracic irradiation therapy. WC performed bronchial arteriography in 9 patients (8 males and 1 female) with lung cancer who received thoracic irradiation (58-72 Gy). Three patients had adenocaminoma. 3 squamous cell carcinoma, 2 small cell carcinoma and 1 large cell carcinoma. Their clinical stages were 6 in stsgc ~JI(B) and 3 in stage IV. Eight of these casts also received chemotherapy by intra-bronchial arterial infusion of anti-cancer agents (Carboplatin and/or Cisplatin). The bmnchial arterial supply was patent except in the one complete remission case (squall CCII carcinoma of stage III(B)). In the tivc cases developing radiation pncumonitis, bronchial atterics demonstrated angiogencsis in the radiation fields, despite which pulmonary artcriography and/or pulmonary perfusion scintigrams showed a dmxascd pulmonary arterial supply. Bronchial tial hemodynamics demonstrated no significant damage in the bronchial artcries by the thoracic irradiation therapy and/or bronchial arterial infusion of anti-cancer agents. It is suggested that patent bronchial arteries atIer radiation therapy promote local m~~rretxcs of lung cancer. In 5 cases, including 2 local relapsed cases and 3 CBSCS showing 00 remark&k reeponsc to radial radiation thempy, WC performed bronchial arterial infusion of anti-cancer agents at& radiation therapy, with good rcsponsm obtained. We conclude that thoracic irradiit& did not damage bronchial ties as comparad with pulmonary atteriea, and that in low1 relapsed and rsdiwcsistant cases bronchial arterial infusion of anti-cancer agents after radiation therapy is a useful approach.
Establishment of a human to okadaic acid
small-cell
lung-cancer
subline
resistant
Takcda Y, Nishio K, Kubota N, Miura K, Morikage T, Ohmori T et al. Pharmacology Diw~sion. Nat Cancer Center Research Inst.. 5-l-l Takji, Chumku, Tokyo 104. b-d J Cancer 1994$8:882-90. Okadaic acid (OA). a specific protein phosphatase inhibitor, has various biological functions. To elucidate the mechanism of OA resistance, WC have established a small-cell lung-cancer sublinc (H69/OAlOO) resistant to the growth-inhibitory effect of OA, this was done by using the parental cell line (H69) and increasing the concentration of OA. H69/OAlOO was about 8 times more resistant to OA than H69. Intracellular retention of the fluorescent OA derivative in H69/OAlOO was the same as that in H69. The catalytic activity of pmtein phosphatase fmm H69/OAlOO was significantly reduced compared with that from H69. The protein phosphatase fmm H69/OAlOO was 3.6 times more resistant to OA than that from H69. We examined the effect of OA on the activity of the immunoprcoipitatcd protein phosphatase type 1 @‘PI) and type 2A (PP2A) from the 2 cell lines. fhe PPI and PP2A from H69/OAlOO showed more resistance to OA than those fmm H69. We next examined the effect of OA on the cell cycle ofH69 and H69/OAloO. In H69,G,!M block was observed at an OA concentration of 30 ngiml whereas in H69/OAICO, no G@ block we observed at concentrations up to 100 rig/ml OA. We finally cvsluated the amount of p34(cdc2) kinasc expression and the phosphorylation status of p34(&2). There was no difference in p34(cdc2) expression behvem H69 and H69/OAlOO at several wnccntrations of OA. However, dephosphorylation of p34(&2) was observed at 30 @ml OA in H69, but not in H69/OAlOO up to 100 @ml OA. These data suggest that the resistance to OA and the resistance of the ccll-cyclc block to OA in H69/OAloO might be due to alteration of protein phosphatasc activity.
Phase 2 study of prolonged administration nation with weekly cisplatia in advanced
of oral etoposklc in combinon-small cell lung cancer
Robert F, Wheeler RH, Molthrop D, Bailey A. Chen S. Birmingham VA Medical Cente,: 7OOSouth 19th Sbwt. Birmingham, AL 35233. Am J Clin Oncol Cancer Clin Trials 1994,17:3836. We administered chemotherapy consistmg of a 21-day course of oral etoposide (50 mglm’iday) and a 3-weekly dose of cisplatin (30-33 mglm’iweek) to 23 chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC). Six patients achieved a partial response (28.6%; 95% confidence interval, 11.3-52.2%), with s median response duration of4 months and a median
Abstracts/Lung
Suramia interferes with auto/paracrine insulin-like growth factor coatmlled pmliferative loop 011 human lung cancer cell lines
Cancer I-
Favoni RE, Ravera F, Pirani P, Ardizmni A, Noonan D, Cupis de A. Depf.of Experimental Phormocolo~, Inst.Naz. per la Ricerca sul Concro, Vt& BenedettoXVlO, 16132 Gmova. Eur J Pharmacol 1994;264:199-206. Human non-small cell lung cancer (N-SCLC), a cmnmon malignancy generally unmanageable by conventional cytotoxic chemotherapy. represents a major world health burden. Suramin, a polyanionic drug which appears to interfere with growth-factor/receptor interaction, has recently been shown to be cytostatic for small cell lung cancer cellp; it may also be effective for NSCLC. As insulin-like growth factor I (IGF-I) is a known progression agent for N-SCLC, we have examined the effects of suramin on the ‘IGF-I system’ in a panel of human N-SCLC cell lines. Calorimetric and thymidinc incorporation assays were used to assess cell chemosensitivity whereas a rsdiwcceptor assay was employed to evaluate IGF-I/receptor binding. Suramin reversibly reduced, in a concentration- and time-dependent manner, the growth of each N-SCLC cell line examined either cultured in serumeontaining or serum-free medium. Furthemmre, suramin caused a concmtration-related inhibition of labeled IGF-I peptidc specific binding on all cell lines studied. Suramin caused a significant reduction in the B(max) values with only weak variations in the affinity constants (K(d)). WC hypothesize that suramin intcrfercmx with IGF-I mitogenic activity is a pathway by which this drug produces its effect in vitro. These data indicate further shrdies on the mechanism of action and pharmacology of suramin in viva *re warranted.
Wall PJ, Rozmgwt E. Imperial Cancer Research Fund, Lincoln i Inn Fields, London FVC2A 3PX Pmc Natl Acad Sci USA 1988,8S:l859-63. In the search for a mora potent bomb&n antagonist, we found [DArg’S Phc’,D-Trp’~,Lcucu”]substanstancc P to be effective in mouse tibroblasts and to inhibit the gmwth of small cell lung cancer, a tumor that secretes bombesin-like peptides that may act as autocrinc growth factors. In murinc Swiss 3T3 cells, ID-Afg’.DPhdPTrp’“~u”]substsncc P proved to be a bomb&n antagonist as judged by the following criteria: (i) inhibition of DNA synthesis induced by gasttinreleasing peptidc and other bombesin-like peptides; (ii) inhibition of ‘“I-laboled gastrin-releasing pcptide binding to the bombesin/gastrin-releasing peptidc receptor; (iii) reduction in cross-linking of the M 75,000-85,000 protein putatively a component of the bambesin/gastrin-releasing peptidc receptor, (iv) blocking of early c&dar events that precede mitogencsis-calcium mobilization and inhibition of cpidermal growth factor binding. [D-Arg’.D-Phc’,DTrp”Leu”]substancc P was 5-fold more potent than the antagonist PArg’PRo’,D-Trp~9,Leu”]substance l? ~~‘PPh~PTrp~qLcu”]substancc P also inhibits mitogenesis induced by vwpressin but not that induced by a variety of other mitogens. Both antagonists reversibly inhibited the growth of small cell lung cancer in vitro in a concentration-dependent manner. Pcptide antagonists could, therefore, have far-reaching therapeutic implications.
Late phase II clinical study of KW-2307 in previously untreated patients witb non-small cell lung cancer Furuse K. Kinuwaki E, Motomiya M, Nishiwaki H, Hascgawa K, Kobaysshi K et al. Department of Inferno/Medicine. National Kinki Central Hospital, Osaka. Jpn J Cancer Chemother 1994;21:1941-7. A late Phase II clinical study of KW-2307, a new vinca alkaloid derivative, in previously untreated patients with non-small cell lung cancer was jointly carried out in 26 medical instihltions. Of 80 enrolled cases, 75 casts were eligible, and PR was attained in 23 cases (30.7%). The main advnsc effect of this drug, leukopenia (ncutmpenia), was observed in 62.7% (83.3% ) of Grade 3 and 4 cases. but they recovered rapidly. In addition to decreased hemoglobin in 67% (Grade 3 in 5.7%) of the cases, adverse effects included slight disorder of hepatic function, anorexia, nausea and vomiting. fever, general fatigue, phlebitis, paresthesia and interstitial pneumonia. Peripheral neuropathy such as paresthesia occurred rarely and was slight, if any.
I2 (1995)
265-329
Bnmcbial arterial bemodynamics after tboracic irradiation therapy in lung cancer patients Nambu Y, Tamamura H, Ohguchi M, Mauri M, Kobayashi Y, Ysmanouchi K et al. Division ofRespiratmyDi.wse, Deportment offntanalMedicine, Karwza~~ Medical Universily, D&g& I-I. Uchinoda. Kahoku-gun, Ishikawa 920-02. Jpn J Thorac LXs 1994,32:644-9. WC evaluated bronchial arterial hemodynamics at?er thoracic irradiation therapy. WC performed bronchial arteriography in 9 patients (8 males and 1 female) with lung cancer who received thoracic irradiation (58-72 Gy). Three patients had adenocaminoma. 3 squamous cell carcinoma, 2 small cell carcinoma and 1 large cell carcinoma. Their clinical stages were 6 in stsgc ~JI(B) and 3 in stage IV. Eight of these casts also received chemotherapy by intra-bronchial arterial infusion of anti-cancer agents (Carboplatin and/or Cisplatin). The bmnchial arterial supply was patent except in the one complete remission case (squall CCII carcinoma of stage III(B)). In the tivc cases developing radiation pncumonitis, bronchial atterics demonstrated angiogencsis in the radiation fields, despite which pulmonary artcriography and/or pulmonary perfusion scintigrams showed a dmxascd pulmonary arterial supply. Bronchial tial hemodynamics demonstrated no significant damage in the bronchial artcries by the thoracic irradiation therapy and/or bronchial arterial infusion of anti-cancer agents. It is suggested that patent bronchial arteries atIer radiation therapy promote local m~~rretxcs of lung cancer. In 5 cases, including 2 local relapsed cases and 3 CBSCS showing 00 remark&k reeponsc to radial radiation thempy, WC performed bronchial arterial infusion of anti-cancer agents at& radiation therapy, with good rcsponsm obtained. We conclude that thoracic irradiit& did not damage bronchial ties as comparad with pulmonary atteriea, and that in low1 relapsed and rsdiwcsistant cases bronchial arterial infusion of anti-cancer agents after radiation therapy is a useful approach.
Establishment of a human to okadaic acid
small-cell
lung-cancer
subline
resistant
Takcda Y, Nishio K, Kubota N, Miura K, Morikage T, Ohmori T et al. Pharmacology Diw~sion. Nat Cancer Center Research Inst.. 5-l-l Takji, Chumku, Tokyo 104. b-d J Cancer 1994$8:882-90. Okadaic acid (OA). a specific protein phosphatase inhibitor, has various biological functions. To elucidate the mechanism of OA resistance, WC have established a small-cell lung-cancer sublinc (H69/OAlOO) resistant to the growth-inhibitory effect of OA, this was done by using the parental cell line (H69) and increasing the concentration of OA. H69/OAlOO was about 8 times more resistant to OA than H69. Intracellular retention of the fluorescent OA derivative in H69/OAlOO was the same as that in H69. The catalytic activity of pmtein phosphatase fmm H69/OAlOO was significantly reduced compared with that from H69. The protein phosphatase fmm H69/OAlOO was 3.6 times more resistant to OA than that from H69. We examined the effect of OA on the activity of the immunoprcoipitatcd protein phosphatase type 1 @‘PI) and type 2A (PP2A) from the 2 cell lines. fhe PPI and PP2A from H69/OAlOO showed more resistance to OA than those fmm H69. We next examined the effect of OA on the cell cycle ofH69 and H69/OAloO. In H69,G,!M block was observed at an OA concentration of 30 ngiml whereas in H69/OAICO, no G@ block we observed at concentrations up to 100 rig/ml OA. We finally cvsluated the amount of p34(cdc2) kinasc expression and the phosphorylation status of p34(&2). There was no difference in p34(cdc2) expression behvem H69 and H69/OAlOO at several wnccntrations of OA. However, dephosphorylation of p34(&2) was observed at 30 @ml OA in H69, but not in H69/OAlOO up to 100 @ml OA. These data suggest that the resistance to OA and the resistance of the ccll-cyclc block to OA in H69/OAloO might be due to alteration of protein phosphatasc activity.
Phase 2 study of prolonged administration nation with weekly cisplatia in advanced
of oral etoposklc in combinon-small cell lung cancer
Robert F, Wheeler RH, Molthrop D, Bailey A. Chen S. Birmingham VA Medical Cente,: 7OOSouth 19th Sbwt. Birmingham, AL 35233. Am J Clin Oncol Cancer Clin Trials 1994,17:3836. We administered chemotherapy consistmg of a 21-day course of oral etoposide (50 mglm’iday) and a 3-weekly dose of cisplatin (30-33 mglm’iweek) to 23 chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC). Six patients achieved a partial response (28.6%; 95% confidence interval, 11.3-52.2%), with s median response duration of4 months and a median