Constitutive production of multiple colony-stimulting factors in patients with lung cancer...
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Abstructs / Lung Cancer I I (1994) 323-344 337 hial. we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-I 1 doa in combination with a fixed cisplatin dose. Prrrienrsnruf Mel/r&: Twenty previously untreated patients with stage IllB or IV non-small&l lung cancer (NSCLC) were treated with CPT-I 1 on days 1,8. and 15 in combination wirh cisplatin 80 mglm’intravenously on day 1. In addition, rhG-CSF (2 g/kg/d) was administered on days 4 to 2 1, except on the days of CPT- I I treatment. The starting dose of CPT-I I was 70 mg/&. and the CPT- I1 dose was escalated in IO-mglm’ increments until the maximum- rolerated dose was reached. Results: Diarrhea was the dose-limiting toxicity aI 90 mg/&. Two of six patirnts experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CFT-I I dose from 80 to 90 mglm’ resulted in a marked increase in the plasma concentration of 7-ethyl- IO- hydmxycamptothecin (SN-38). Occurrence of diarrhea was well cor- relatedwith thepeakplasmaconcentration(Cmax)ofSN-38(P = .035). There were 10 partial response.5 (50%) among 20 paIients. Conclusion: The recommended dose for phase II studies is 80 mglm* ofCPT-I 1, and 80mg/m’ofcisplatinplusrhG-CSF. Wirh theuseofrhC-CSF, theCPT- I I dose can be increased 33 % above that in the original regimen (60 mgi m* of CPT-I I and 80 mglm of cisplatin). lmmunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer Zangemeister-Wittke U. Collinson AR, Frosch B, Waibe.1R. Schenker T, Stahel RA. Division of Oncology, University Hospital. 8044Zurich. Br J Cancer 1994;69:32-9. The present study describes a comparison of two potent immunoloxins which utilise an identical targeting component, a monoclonalantibody(SEN7)speciticforsmallcell lungcancer(SCLC). conjugated to two different effector components. blocked ricin (bR) and Pseudomonasexotoxin A (PE). SEN7 recognisesa novel epitope on the neural cell adhesion molecule (NCAM) which is highlymiatd with SCLC. The immunotoxinsSEN7-PEandSEN7-bRwereselectivelyand pofenrly active against a number of SCLC cell lines. of both classic and variant morphologies, inhibiting Ihe incorporation of PHjleucine with IC, values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial ratesofproteinsynthesisinhlbitionoccurred with &valuesof6.5 h for SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced Ihecy~otoxicactivityofthewr?aklyactiveSEN7-ricinA-chain by2, IOO- fold and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logsofclonogenic SW2 tumour cells were selectively eliminated from Ihe cultures during continuous exposure to the immunoloxms SEN7-PE and SEN7-bR respectlvzly. while antigen-negative cells required up 10 l,CCO-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR trealmenl in Ihe cultures did not express NCAM and consequently were noI selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE show& no alteration in NCAM expression bur were more resistant to intoxicalion mediated by PE. Tht~ cells were still sensitive to SEN7-bR. Constitutive production of multiple colony-stimulting factors in pafients with lung cancer associated with neutrophilia Adachi N, Yamaguchi K, Morikawa T. Suzuki M, Matauda I, Abe K. Growth Factor Division, Nat1 Cancer Center Research Inst. Tsukiji S- I-I, Chuo-ku. Tokyo 104. Br J Cancer 1994;69: 125-9. Pmduclion of colony-stimulating factor (CSF) was examined in Ihree patients with lung cancer associated with neutrophilia. All three patients presented a marked increa.. m neutroptnl count (26,000- 39,COO I ‘ ) that continued al least for 3 weeks and rapidly disappearti after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissw stimulated the colony formation of bone marrow myeloid progemtor cells in vitro. Northern blot analysis of poly(A)’ RNA from the tumour tissues revealedaconstitutiveexpreseion of granulocyte (G). macrophage (M), and granulocyte-macrophage (GM) CSF genes in all turnours. Immunoassay specific for these CSFs revealed that G-and M-CSF immunoreactivily was detected in all CM and GM-CSF pro&n in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or ncnr-normal range afier operalion. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither sllmularrd haematopoictic colony formarion nor contamed immunoreactivr CSFs. These results indicated that the neutrophdia found in the three patients was prohahly caused hy con&u& producrmn of multiple CSFs by lung cancer crlls. Inhibitory effects ofcholera toxin on in vitro growth of human lung cancer cell lines Kiura K, Watarai S, ShibPyamaT. Ohnoshi T, Kimura 1. Yasuda T. /n.rr Cellular and Molecular Biology, Okayutna lJniwr.sity Medical School, 2-S-I Shikotu-rho. Okuyuma 700. Anti-Cancer Drug Res 1993;8:417- 28. Cholera toxm (CT) inhibited the growth of three out of IO small cell lung cancer (SCLC) cell lines and two out of seven non-small cell lung cancer (NSCLC) cell lines when tested by 3-[4,5dimethylthiazol- 2-ylj-2,Sdiphenyltetrliumbmmide(MTT)assay. TheseCT-sensitive as well as CT-resistant cell lines bound well to the non-toxic CT-B subunit-fluoresceinisothiocyanateconjugate(FITC-CTB)whenassayed by llow cytometry. Using the reaction of horseradish peroxidasr- conjupatal CT-B (HRP-CTB) on thin-layer chromatography (TLC), we analyzed gangliosides extracted from SCLC cell hnes. CT-resistanl SBC-I, minimally CT-sensitive SBC-3 and CT-sensitive SBC-5. HRP- CTB was found 10 react not only with GM I, hur also wlrh Fuc-GM 1, GDlb and other gangliosidrs on TLC. Although CT-rrslslanl SBC-I cells bound well to FITC-CTB. the binding of gagliosidcs rxlracted from SBC- I cells to HRP-CTB was markedly decrea.4 when compared 10 those from CT-sensitive SBCJ cells. The CT resistance of the minimally CT-sensitive SBC-3 cell lines, which binds wakly FITC- CTB and HRP-CTB. was partially reversed by exogenous G.Ml pre~reatmmt. ~aob.~rvationssuggestthattheamountofgangIiosid~s, such aa GM 1, FucCM I and GDI b. on the cells, rather than the CT- hinding abilily 10 the calls. plays a major role in cytoloxiclly by CT. Urinary-derived monocyte-colony stimulating factor (P-100) following treatment with carboplatin and etoposide in small cell lung cancer (SCLC) Van HoefMEHM, Redford JA. Jones A, Smith IE, Earl HM. Wall PJ 21 al. Ann Oncol 1993;4: 877-81. Backgroundz The hrmatopoietic growth factor P-100 is a monocytesolony stimulating factor purified from human unne and has been reported to reduce nwtmpenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patienls receivingintensivecbemothempyforSCLC. Yudyderign:Chrmorherapy consisted offour 28 daycyclesofcarboplatin (C)600 mg1m’ i.v. onday I ofcycle 1 + 2and3OOmgl&i.v. onday I ofcycle + 4andetoposide (E) 120 mglm’i.v. on day I-3 ofeach cycle. Pa&znts were random&d 10 receive P-100 for ten days following chemotherapy during either rhr
Transcript of Constitutive production of multiple colony-stimulting factors in patients with lung cancer...
Abstructs / Lung Cancer I I (1994) 323-344 337
hial. we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-I 1 doa in combination with a fixed cisplatin dose. Prrrienrs nruf Mel/r&: Twenty previously untreated patients with stage IllB or IV non-small&l lung cancer (NSCLC) were treated with CPT-I 1 on days 1,8. and 15 in combination wirh cisplatin 80 mglm’ intravenously on day 1. In addition, rhG-CSF (2 g/kg/d) was administered on days 4 to 2 1, except on the days of CPT- I I treatment. The starting dose of CPT-I I was 70 mg/&. and the CPT- I1 dose was escalated in IO-mglm’ increments until the maximum- rolerated dose was reached. Results: Diarrhea was the dose-limiting toxicity aI 90 mg/&. Two of six patirnts experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CFT-I I dose from 80 to 90 mglm’ resulted in a marked increase in the plasma concentration of 7-ethyl- IO- hydmxycamptothecin (SN-38). Occurrence of diarrhea was well cor- relatedwith thepeakplasmaconcentration(Cmax)ofSN-38(P = .035). There were 10 partial response.5 (50%) among 20 paIients. Conclusion: The recommended dose for phase II studies is 80 mglm* ofCPT-I 1, and 80mg/m’ofcisplatinplusrhG-CSF. Wirh theuseofrhC-CSF, theCPT- I I dose can be increased 33 % above that in the original regimen (60 mgi m* of CPT-I I and 80 mglm of cisplatin).
lmmunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer Zangemeister-Wittke U. Collinson AR, Frosch B, Waibe.1 R. Schenker T, Stahel RA. Division of Oncology, University Hospital. 8044Zurich. Br J Cancer 1994;69:32-9.
The present study describes a comparison of two potent immunoloxins which utilise an identical targeting component, a monoclonalantibody(SEN7)speciticforsmallcell lungcancer(SCLC). conjugated to two different effector components. blocked ricin (bR) and Pseudomonas exotoxin A (PE). SEN7 recognises a novel epitope on the neural cell adhesion molecule (NCAM) which is highlymiatd with SCLC. The immunotoxinsSEN7-PEandSEN7-bRwereselectivelyand pofenrly active against a number of SCLC cell lines. of both classic and variant morphologies, inhibiting Ihe incorporation of PHjleucine with IC, values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial ratesofproteinsynthesisinhlbitionoccurred with &valuesof6.5 h for SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced Ihecy~otoxicactivityofthewr?aklyactiveSEN7-ricinA-chain by2, IOO- fold and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logsofclonogenic SW2 tumour cells were selectively eliminated from Ihe cultures during continuous exposure to the immunoloxms SEN7-PE and SEN7-bR respectlvzly. while antigen-negative cells required up 10 l,CCO-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR trealmenl in Ihe cultures did not express NCAM and consequently were noI selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE show& no alteration in NCAM expression bur were more resistant to intoxicalion mediated by PE. Tht~ cells were still sensitive to SEN7-bR.
Constitutive production of multiple colony-stimulting factors in pafients with lung cancer associated with neutrophilia Adachi N, Yamaguchi K, Morikawa T. Suzuki M, Matauda I, Abe K. Growth Factor Division, Nat1 Cancer Center Research Inst. Tsukiji S- I-I, Chuo-ku. Tokyo 104. Br J Cancer 1994;69: 125-9.
Pmduclion of colony-stimulating factor (CSF) was examined in Ihree patients with lung cancer associated with neutrophilia. All three patients presented a marked increa.. m neutroptnl count (26,000- 39,COO I ‘) that continued al least for 3 weeks and rapidly disappearti after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissw stimulated the colony formation of bone marrow myeloid progemtor cells in vitro. Northern blot analysis of poly(A)’ RNA from the tumour tissues revealedaconstitutiveexpreseion of granulocyte (G). macrophage (M), and granulocyte-macrophage (GM) CSF genes in all turnours. Immunoassay specific for these CSFs revealed that G-and M-CSF immunoreactivily was detected in all CM and GM-CSF pro&n in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or ncnr-normal range afier operalion. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither sllmularrd haematopoictic colony formarion nor contamed immunoreactivr CSFs. These results indicated that the neutrophdia found in the three patients was prohahly caused hy con&u& producrmn of multiple CSFs by lung cancer crlls.
Inhibitory effects ofcholera toxin on in vitro growth of human lung cancer cell lines Kiura K, Watarai S, ShibPyama T. Ohnoshi T, Kimura 1. Yasuda T. /n.rr Cellular and Molecular Biology, Okayutna lJniwr.sity Medical School, 2-S-I Shikotu-rho. Okuyuma 700. Anti-Cancer Drug Res 1993;8:417- 28.
Cholera toxm (CT) inhibited the growth of three out of IO small cell lung cancer (SCLC) cell lines and two out of seven non-small cell lung cancer (NSCLC) cell lines when tested by 3-[4,5dimethylthiazol- 2-ylj-2,Sdiphenyltetrliumbmmide(MTT)assay. TheseCT-sensitive as well as CT-resistant cell lines bound well to the non-toxic CT-B subunit-fluoresceinisothiocyanateconjugate(FITC-CTB)whenassayed by llow cytometry. Using the reaction of horseradish peroxidasr- conjupatal CT-B (HRP-CTB) on thin-layer chromatography (TLC), we analyzed gangliosides extracted from SCLC cell hnes. CT-resistanl SBC-I, minimally CT-sensitive SBC-3 and CT-sensitive SBC-5. HRP- CTB was found 10 react not only with GM I, hur also wlrh Fuc-GM 1, GDlb and other gangliosidrs on TLC. Although CT-rrslslanl SBC-I cells bound well to FITC-CTB. the binding of gagliosidcs rxlracted from SBC- I cells to HRP-CTB was markedly decrea.4 when compared 10 those from CT-sensitive SBCJ cells. The CT resistance of the minimally CT-sensitive SBC-3 cell lines, which binds wakly FITC- CTB and HRP-CTB. was partially reversed by exogenous G.Ml pre~reatmmt. ~aob.~rvationssuggestthattheamountofgangIiosid~s, such aa GM 1, FucCM I and GDI b. on the cells, rather than the CT- hinding abilily 10 the calls. plays a major role in cytoloxiclly by CT.
Urinary-derived monocyte-colony stimulating factor (P-100) following treatment with carboplatin and etoposide in small cell lung cancer (SCLC) Van HoefMEHM, Redford JA. Jones A, Smith IE, Earl HM. Wall PJ 21 al. Ann Oncol 1993;4: 877-81.
Backgroundz The hrmatopoietic growth factor P-100 is a monocytesolony stimulating factor purified from human unne and has been reported to reduce nwtmpenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patienls receivingintensivecbemothempy forSCLC. Yudyderign:Chrmorherapy consisted offour 28 daycyclesofcarboplatin (C)600 mg1m’i.v. onday I ofcycle 1 + 2and3OOmgl&i.v. onday I ofcycle + 4andetoposide (E) 120 mglm’ i.v. on day I-3 ofeach cycle. Pa&znts were random&d 10 receive P-100 for ten days following chemotherapy during either rhr
