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Altered subcellular distribution of topoisomerase IIα in a drug-resistant human small cell lung cancer cell line
Abstracts/
Lung Cancer II
and a higher rqonse rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a relevant regimen in advanced NSCLC.
Treatment of unremtabk nonsmallcell lungcancer(NSCLC) with awboplatin and chronic daily administration of oral etoposide Hirabayashi
M. Tanaka Y, Yoshida H, Nakagawa
M, Kuno K.
Departmenr of Clinical Physiology, Chwr D&are Research Indue, Kyto University, Kyofo. Jpn J Cancer Chemother 1994;21: 53-8.
CBDCA has only modeat activity against NSCLC. but it is less toxic than cisplatin (CDDP). And CB DCA haa a provea synergistic effectwithetoposide. Oatheotherhmd,~~i&is~cheduledependcat and when give daily pcros has activity against several tumors. So we conducted a trial to evaluate the effiiucy of a combination of CBDCA and chronic daily administration of oraI ctoposide for previously untreated unresectable NSCLC. The treatment schedule consisted of CBDCA 400 mg/d on day I and chronic daily administration of oral etoposide of 50 mg/day/body for 21 consecutive days every 28 days. Twenty-nineof30enrolledpatientswereeligible. Thereaponseratewas 27.6 96 (95 96 confidence interval: 1 I. I - 43.9 %). 7he median survival time was 405 dsys. The primary toxicity was myelosuppression: leukopenia, neutropenia, anemia and thmmbocytopenia of Grade 3 of 4 were 14.7%. 29.4%. 26.556, and 5.996, respectively. No bleeding episodes or toxic death were observed. Nonhematologic toxicity was slight, and therewa?wseveregrstrointestinal toxicity.Thiscombination was effective against NSCLC with tolerable toxicity and an ‘easily tolerated outpatient regimen’.
(1994)
323-344
341
deoxydoxontbicin (I-WXO) in advanced and -table non-small cell lungc.ancer(NSCLC). Porierusandkluhodc:Twenty-th~patients with advanced and measurable NSCLC were treated with 80 mg/& IDOXO every 3 we&. Results: Three. partial remissions (13 %, 95% confidcace interval: 2.8-33.6%) lasting 3.5, 5, and 6.5 months, were observed. Ninepatients(39’X)demonstratednochangeofshortduration and 1I (48 56)patients had progressive disease. Hematologic side effects were mild to moderate without any WHO grade 2 leuko- or thmmbocytopenia. No severe nonhematologic toxicities occurred. Conclusions: I-DOXO has only minimal efficacy in NSCLC.
Altered suhcellular diitrihution of topoisomerase Ila in a drug-resistant human small cell lung amcer cell line Feldhoff PW, Mirski SEL, Cole SPC, Sullivan Dbl. James Graham Brown Cancer Center, Uniwrsiry of L.oui.wiIle. 529 South Jackson Sfreer, Louisville, KY 40292. Cancer Res 1994;54: 75662.
A drug-resistant human small cell lung cancer cell line, I l209/ V6. selected in the presence of increasing concentrations of 9-(4.6-Oethylidene-ll-D-glucopynnosyl)-4’demethylcpipodophyllotoxin (VP16) from parental H209 cells. is 22-, 9-. and I-fold resistant to VP-16. 4’-(9-acridinylamino)methanesulfon-m-anisidide, and doxorubicin, respectively. but not cross-resistant to 1,4dihydmxy-5.8-bis((2-[(2hydroxyethyl)amino]ethyl)-amino)-9, IO-anthracenedione. These cells do not overexpress P-gl ycopmtein or the multidntg resistancsacsociated protein. Immunoblotting demonstrates that HZ09 cells contain the M(r) 170,ooO isoform of topoisomerase II (top0 II). while H209/V6 cells haveaM 160$00enzymehutnoneoftheM(r) 170,OOOisoform. The cell lines have equal amounts of topo HA. The H209/V6 cells have a 5fold decrease in total immunoreactive topo lb. The catalytic and VP16-induced DNA cleavage activities of the topo II present in 0.35 M NaCl nuclutrextractsaredecrd 2- to 3-fold in thedrug-resistant cell line. This decrease in enzymatic activity is not consistent with either the 22-fold VP- I6 resistance of the H209/V6 cell line or the approximately 5-fold decrease in immunoreactive topo 11~1in the cells. The M(r) 160.000 &form fmm the H209/V6 cell line and the M(r) 170,000 enzyme from the parental cell line were purified so that the enzymatic activity of the 2 isofonc could be evaluated. The catalytic activities of the purified isofom were found to be very similar. The drug-induced DNA cleavage activity of the M(r) 160,ooO enzyme was reduced compared to the M(r) 17O,C@Oenzyme. However, as with the nuclear extracts, the differences in enzymatic activity of the purified enzymes are considerahly less than the level of drug resistance. Investigations of thesubcellularlocalization oftopoll by immunocytochemical techniques and cytoplasm/nuclear fractionation studies demonstrated that the M(r) 160,000 topo Ila-relatedenzymeisprirnarily localized in thecytoplPsm, while the M(r) 170.000 topo Ila enzyme and topo II8 are located in the nucleus. Thesedata imply that the deleted sequence in the M(r) 160,OCQ enzyme is not ntressPry for catalytic activity but is required to ficilitate nuclear localization.
A phase II trial of alternating chemotherapy in patients with inoperable non-small cell lung cancer Howard LM, Kasimis BS, Cramer EM, Ruddy P, Hiremath V, Pokomey ES. Veterans wairs Medical Center, 385 Ttnnonr Awnuc. EavtOrange, NJ07018.AmJClinChcolCancerClinTrials1994;17:835. We asses& the efficacy and toxicity of alternating non-crossresistant chemotherapy in the treatment ofadvanced NSCLC. Cyclesof cisplatin. methotrexate. doxorubicin, and cyclopbosphamide were alternated monthly with cisplatin and etoposide. Patients bad measurable disease, ECGG performance status O-3, no previous chemotherapy, and stage II (inoperable). Ill, or IV disease. without brain me&stases. Between 1988 and 1990, 28 patients were entered in the study: 20 patients (71%) had stage IV disease, 19 (68%) were evaluable for response and toxicity; 4 (21%) responded. There were 3 partial responders (16%) and 1 complete responder (5 %). The mean duration of response was 60.5 weeks (range: 32-105 + weeks), and the median time to progression was I2 weeks (range: S-105 + weeks). The median survival time for all 28 patients was 24 weeks (range: 3-153 + weeks). The most significant toxicity was grade 3-4 leukopenia experienced by 63 % of patients, but there were no episodes of sepsis and no treatmentrelateddeaths. Thisre.gimcnofaltematingcyclesofcisplatincontaining chemotherapy isspfe, but itsefticacy isnotsuperiortoothercomhination Biologic and clinical effects of continuous infusion interImkin2 in patients with non-small eelI lung can= chemotherapy regimens. Ardizzoni A. Bonavia M. Viale M. Baldini E. Mereu C. Vema A et al.
Phase II study of 4’4odo4-deoxydoxorubicin
in patients with advanced, measurable non-small cell lung cancer Eberhardt W. Niederle N. Wilke H, Weidmann B. Henss H, Engelhardt R ti al. lnnere Klinik und Poliklinik. Wesrdeudus Tumonentrum. Hufelandsrrawr 55, D-45157Essen. Onkologie 1993;16:446-8. Balground: On the basis of preclinical data and phase I trials, a disease-orientated phase II trial was conducted with 4’-iodo-4’-
Depanmenr o/Medical Oncology, Isro. Narionale Ricerca sul Cancro, Viale Benedeuo XV, 10, 16132 Genoa. Cancer 1994;73:1353-60. Background. Interleukin-2 (IL-2) has shown antitumor activity
in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is signiticnnt. particularly at the cardiorespiratory level. Mtihodv. Toted feasibility, antitumoractivity, pulmonary and systemic immunologic effects, and pulmonary function changes ofcontinuous- infusion recombinant IL-2 give0 to patients with
Lung Cancer II
and a higher rqonse rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a relevant regimen in advanced NSCLC.
Treatment of unremtabk nonsmallcell lungcancer(NSCLC) with awboplatin and chronic daily administration of oral etoposide Hirabayashi
M. Tanaka Y, Yoshida H, Nakagawa
M, Kuno K.
Departmenr of Clinical Physiology, Chwr D&are Research Indue, Kyto University, Kyofo. Jpn J Cancer Chemother 1994;21: 53-8.
CBDCA has only modeat activity against NSCLC. but it is less toxic than cisplatin (CDDP). And CB DCA haa a provea synergistic effectwithetoposide. Oatheotherhmd,~~i&is~cheduledependcat and when give daily pcros has activity against several tumors. So we conducted a trial to evaluate the effiiucy of a combination of CBDCA and chronic daily administration of oraI ctoposide for previously untreated unresectable NSCLC. The treatment schedule consisted of CBDCA 400 mg/d on day I and chronic daily administration of oral etoposide of 50 mg/day/body for 21 consecutive days every 28 days. Twenty-nineof30enrolledpatientswereeligible. Thereaponseratewas 27.6 96 (95 96 confidence interval: 1 I. I - 43.9 %). 7he median survival time was 405 dsys. The primary toxicity was myelosuppression: leukopenia, neutropenia, anemia and thmmbocytopenia of Grade 3 of 4 were 14.7%. 29.4%. 26.556, and 5.996, respectively. No bleeding episodes or toxic death were observed. Nonhematologic toxicity was slight, and therewa?wseveregrstrointestinal toxicity.Thiscombination was effective against NSCLC with tolerable toxicity and an ‘easily tolerated outpatient regimen’.
(1994)
323-344
341
deoxydoxontbicin (I-WXO) in advanced and -table non-small cell lungc.ancer(NSCLC). Porierusandkluhodc:Twenty-th~patients with advanced and measurable NSCLC were treated with 80 mg/& IDOXO every 3 we&. Results: Three. partial remissions (13 %, 95% confidcace interval: 2.8-33.6%) lasting 3.5, 5, and 6.5 months, were observed. Ninepatients(39’X)demonstratednochangeofshortduration and 1I (48 56)patients had progressive disease. Hematologic side effects were mild to moderate without any WHO grade 2 leuko- or thmmbocytopenia. No severe nonhematologic toxicities occurred. Conclusions: I-DOXO has only minimal efficacy in NSCLC.
Altered suhcellular diitrihution of topoisomerase Ila in a drug-resistant human small cell lung amcer cell line Feldhoff PW, Mirski SEL, Cole SPC, Sullivan Dbl. James Graham Brown Cancer Center, Uniwrsiry of L.oui.wiIle. 529 South Jackson Sfreer, Louisville, KY 40292. Cancer Res 1994;54: 75662.
A drug-resistant human small cell lung cancer cell line, I l209/ V6. selected in the presence of increasing concentrations of 9-(4.6-Oethylidene-ll-D-glucopynnosyl)-4’demethylcpipodophyllotoxin (VP16) from parental H209 cells. is 22-, 9-. and I-fold resistant to VP-16. 4’-(9-acridinylamino)methanesulfon-m-anisidide, and doxorubicin, respectively. but not cross-resistant to 1,4dihydmxy-5.8-bis((2-[(2hydroxyethyl)amino]ethyl)-amino)-9, IO-anthracenedione. These cells do not overexpress P-gl ycopmtein or the multidntg resistancsacsociated protein. Immunoblotting demonstrates that HZ09 cells contain the M(r) 170,ooO isoform of topoisomerase II (top0 II). while H209/V6 cells haveaM 160$00enzymehutnoneoftheM(r) 170,OOOisoform. The cell lines have equal amounts of topo HA. The H209/V6 cells have a 5fold decrease in total immunoreactive topo lb. The catalytic and VP16-induced DNA cleavage activities of the topo II present in 0.35 M NaCl nuclutrextractsaredecrd 2- to 3-fold in thedrug-resistant cell line. This decrease in enzymatic activity is not consistent with either the 22-fold VP- I6 resistance of the H209/V6 cell line or the approximately 5-fold decrease in immunoreactive topo 11~1in the cells. The M(r) 160.000 &form fmm the H209/V6 cell line and the M(r) 170,000 enzyme from the parental cell line were purified so that the enzymatic activity of the 2 isofonc could be evaluated. The catalytic activities of the purified isofom were found to be very similar. The drug-induced DNA cleavage activity of the M(r) 160,ooO enzyme was reduced compared to the M(r) 17O,C@Oenzyme. However, as with the nuclear extracts, the differences in enzymatic activity of the purified enzymes are considerahly less than the level of drug resistance. Investigations of thesubcellularlocalization oftopoll by immunocytochemical techniques and cytoplasm/nuclear fractionation studies demonstrated that the M(r) 160,000 topo Ila-relatedenzymeisprirnarily localized in thecytoplPsm, while the M(r) 170.000 topo Ila enzyme and topo II8 are located in the nucleus. Thesedata imply that the deleted sequence in the M(r) 160,OCQ enzyme is not ntressPry for catalytic activity but is required to ficilitate nuclear localization.
A phase II trial of alternating chemotherapy in patients with inoperable non-small cell lung cancer Howard LM, Kasimis BS, Cramer EM, Ruddy P, Hiremath V, Pokomey ES. Veterans wairs Medical Center, 385 Ttnnonr Awnuc. EavtOrange, NJ07018.AmJClinChcolCancerClinTrials1994;17:835. We asses& the efficacy and toxicity of alternating non-crossresistant chemotherapy in the treatment ofadvanced NSCLC. Cyclesof cisplatin. methotrexate. doxorubicin, and cyclopbosphamide were alternated monthly with cisplatin and etoposide. Patients bad measurable disease, ECGG performance status O-3, no previous chemotherapy, and stage II (inoperable). Ill, or IV disease. without brain me&stases. Between 1988 and 1990, 28 patients were entered in the study: 20 patients (71%) had stage IV disease, 19 (68%) were evaluable for response and toxicity; 4 (21%) responded. There were 3 partial responders (16%) and 1 complete responder (5 %). The mean duration of response was 60.5 weeks (range: 32-105 + weeks), and the median time to progression was I2 weeks (range: S-105 + weeks). The median survival time for all 28 patients was 24 weeks (range: 3-153 + weeks). The most significant toxicity was grade 3-4 leukopenia experienced by 63 % of patients, but there were no episodes of sepsis and no treatmentrelateddeaths. Thisre.gimcnofaltematingcyclesofcisplatincontaining chemotherapy isspfe, but itsefticacy isnotsuperiortoothercomhination Biologic and clinical effects of continuous infusion interImkin2 in patients with non-small eelI lung can= chemotherapy regimens. Ardizzoni A. Bonavia M. Viale M. Baldini E. Mereu C. Vema A et al.
Phase II study of 4’4odo4-deoxydoxorubicin
in patients with advanced, measurable non-small cell lung cancer Eberhardt W. Niederle N. Wilke H, Weidmann B. Henss H, Engelhardt R ti al. lnnere Klinik und Poliklinik. Wesrdeudus Tumonentrum. Hufelandsrrawr 55, D-45157Essen. Onkologie 1993;16:446-8. Balground: On the basis of preclinical data and phase I trials, a disease-orientated phase II trial was conducted with 4’-iodo-4’-
Depanmenr o/Medical Oncology, Isro. Narionale Ricerca sul Cancro, Viale Benedeuo XV, 10, 16132 Genoa. Cancer 1994;73:1353-60. Background. Interleukin-2 (IL-2) has shown antitumor activity
in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is signiticnnt. particularly at the cardiorespiratory level. Mtihodv. Toted feasibility, antitumoractivity, pulmonary and systemic immunologic effects, and pulmonary function changes ofcontinuous- infusion recombinant IL-2 give0 to patients with