non-p-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: evidence for...

1
135 yttrium-aluminum garnet laser resection of a limited-stage peripheral adenocarcinoma of the lung accomplished in an elderly man with serious chronic obstructive pulmonary disease. TNM staging and long-term follow-up after sleeve resection for broacbogenic tumors Van SchilPE, De 1aRiviere AB, Knaepen PJ, Van Swieten HA, Defauw JJ, Van den Bosch JM. Deparmenr of Thoracic Surgery, Antoniushos- pifal.Postbur25OO.3430EMNieuwegein. AnnThoracSurg 1991;52:1- 0961101. From 1960 to 1989, 145 patients (132 men and 13 women) with a mean age of 60.3 years underwent sleeve lobectomy or sleeve resection ofa main bronchus for a bronchogenic tumor. Squamous cell carcinoma was predominantly found (116 patients, 80.0%), followed by carcinoid tumor in 13 patients (9.0%). Postoperative staging was: stage I, 61 patienu(42.1%):stageI1,47(32.4%);stageIIIA,33(22.8%);andstage IIIB, 4 (2.7%). Thirty-day mortality was 4.8% (7 patients). Follow-up was completeexcept for 1patient who was lost to follow-up4 yearsafter operation. For the whole group, 5, lo-. and I5-year survival rates were 49%. 37%,and 18%,respectively. Better survival was notedin patients with carcinoid tumor and squamous cell carcinoma. Considering 112 patients with T2 and T3 squamous cell carcinoma, 5- and IO-year survival rates for NO disease (52 patients) were 59% and 47%. for Nl disease (5 1 patients) 21% and 0%. and for N2 disease (9 patients) 4.4% and 0%. Differences between Nl and N2 disease were not statistically significant. Survival after sleeve resection is best for carcinoid tumors and squamous ceil carcinoma with negative nodes. Presence of Nl or N2 disease significantly worsens prognosis. with no lo-year survivors and no difference between Nl and N2 status. body C219 (S. E. L. Mirski et al., Cancer Res., 47: 2594, 1987). In the present study, we have used the polymemse chain reaction to verify that H69AR cells do not overexpress P-glycoprotein. Further, transport studies with radiolabeled daunomycin, VP-16, and vinblastine demon- strate that differences in net drug accumulation or efflux are not part of the resistance phenotype of H69AR cells. To determine if H69 and H69AR cells differ in their susceptibility to drug-induced DNA dam- age, DNA single-strand breaks (SSB) generated by VP-16 and Adri- amycin were measured using the alkaline filter elution assay. Readily detectable SSB were produced in intact H69 cells by 5 pM VP-16, but 100 PM drug was required to cause similar damage in H69AR cells. H69AR cells were also resistant to SSB induction by Adriamycin. The formation of SSB by VP-16 was similarly reduced in isolated H69AR nuclei, indicating that resistance to this drug resides, at least in part, in the nucleus. No significant differences were observed in the rate or extent of repair of VP-16-induced DNA SSB in H69 and H69AR cells. The reduced susceptibility to drug-induced SSB may result from alterations in topoisomerase II, since less immunoreactive topoisom- erase II was found in H69AR cells compared to H69 cells. However, changes in topoisomerase II cannot explain the resistance of H69AR cells to such drugs as the Vinca alkaloids and gramicidin D, indicatmg that multiple mechanisms contribute to drug resistance in this small cell lung cancer cell line. Ultrasonic surgical aspirator for lung resection Verazin GT, Regal A-M, Antkowiak JG, Parvez Z, Takita H. Division of Thoracic Surgery and Oncology, Roswell Park Cancer Institute, Elm andCarltonSfreets,Buffalo, NY 14263. AnnThoracSurg 1991:52: 787- 90. The ultrasonic surgical aspirator was originally developed for neuro- surgical procedures and hepatic resections. Ultrasonic vibration at the tip of the instrument results in lysis of the parenchymal cells, leaving more resistant fibrous tissue such as blood vessels and bronchi intact and. thus, minimizing blood loss. We have studied the feasibility of applying the ultrasonic surgical aspirator for segmental and subsegmen- tal lung resection for primary and metastatic neoplasms of the lung. Over the past 5 years, 27 patients underwent segmental or limited lung resection using the ultrasonic surgical aspirator. Except for prolonged air leak in 6 patients postoperatively, no other serious morbidity was noted. We observed several advantages: (1) the ultrasonic surgical aspirator dissects out the pulmonary vessels and bronchi, allowing the surgeon to perform segmental and subsegmental resections with mini- mal blood loss, (2) it permits lung-sparing operation for centrally located tumors that would otherwise have required lobectomy, and (3) itallowsdirectvisuali~tionoflungparenchymaduringdissection,lhus assuring grossly adequate margins. Chemotherapy Non-P-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: Evidence for decreased susceptibility to drug- induced DNA damage and reduced levels of topoisomerase II Cole SPC, Chanda ER, Dicke FP, Gerlach JH, Mirski SEL. Cancer Research Laboratories. Queen’s University, Kingston, Ont. K7L 3N6. Cancer Res 1991;51:3345-52. Data obtained from clinical samples suggest that non-P-glycoprotein mechanisms of multidrug resistance are likely to be important in small cell lung cancer. The H69AR cell line was derived from the H69 small cell lung cancer cell line by selection in doxorubicin (adriamycin) and does not overexpress P-glycoprotein as detected by monoclonal anti- Teniposide and etoposide in previously untreated small-cell lung cancer: A randomized study Bork E, Ersboll J, Dombemowsky P, Bergman B, Hansen M, Hansen HH. Department of Oncology 5072, Finsen InstitutelRigshospitalet. 9 Blegdamsvej, DK-2100 Copenhagen. J Clin Oncol 1991;9:1627-31. A randomized study comparing teniposide (VM-26) and etoposide (VP-16) was performed to investigate whether there are any differences in theactivityandtoxicityofthese twoanalogsinsmall-cell lungcancer (SCLC). Only previously untreated patienti with SCLC were included; 46 and 48 patients receiving VP-16 and VM-26, respectively, are assessable for response. There were no differences between the two groups witi respect to extent of disease, median age, and performance status (PS). The initial doses were for both compounds 70 mg/m’ inu’avenously (IV) daily for 5 days every 3 weeks. After inclusion of 25 patients in the study, the doses were increased to 80 mg/m’ for VM-26 and 90 mg/m* for VP-16 because of differences in toxicity. VM-26 caused more hematologic toxicity than VP-16 throughout the study. The overall responses (complete response [CR] plus partial response. FRI) were 65% for VP-16 and 71% for VM-26, with CR occurring in 24% and 23%. respectively, for the two compounds. Median survival was 8.5 months for VP-16-treated patients versus 11.3 months for VM- 26-meated patients (P = .58). It is concluded that both VP-16 and VM- 26 are highly active single agents in SCLC. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cispiatin Kasahara K. Fujiwara Y. Nishio K. Ohmori T. Sugimoto Y. Komiya K et al. Pharmacology Division, National Cancer Center Research In- stitute. Tsukijij-l-1, Chuo-ku, Tokyo 104. Cancer Res 1991;51:3237- 42. We have established cis-diamminedichloroplatinum(I1) (cisplatin) resistanthumansmallcelllungcancercell lines,H69/CDDP,,andH69/ CDDP, toinvestigatethemechanism ofacquiredresistance tocisplatiu. H69/CDDP,, and H69/CDDP were 6- and 11 -fold resistant to cispiatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4- fold). 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2- methyl-5-pyrimidinyl)methyl]-1-(2-chlorcetiyl) -1. nitmsourea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand cross-link formations, determined by filter elution assay in H69/CDDP,, and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links

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Page 1: Non-P-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: Evidence for decreased susceptibility to drug-induced DNA damage and reduced levels of topoisomerase

135

yttrium-aluminum garnet laser resection of a limited-stage peripheral adenocarcinoma of the lung accomplished in an elderly man with serious chronic obstructive pulmonary disease.

TNM staging and long-term follow-up after sleeve resection for broacbogenic tumors Van SchilPE, De 1aRiviere AB, Knaepen PJ, Van Swieten HA, Defauw JJ, Van den Bosch JM. Deparmenr of Thoracic Surgery, Antoniushos- pifal.Postbur25OO.3430EMNieuwegein. AnnThoracSurg 1991;52:1- 0961101.

From 1960 to 1989, 145 patients (132 men and 13 women) with a mean age of 60.3 years underwent sleeve lobectomy or sleeve resection ofa main bronchus for a bronchogenic tumor. Squamous cell carcinoma was predominantly found (116 patients, 80.0%), followed by carcinoid tumor in 13 patients (9.0%). Postoperative staging was: stage I, 61 patienu(42.1%):stageI1,47(32.4%);stageIIIA,33(22.8%);andstage IIIB, 4 (2.7%). Thirty-day mortality was 4.8% (7 patients). Follow-up was completeexcept for 1 patient who was lost to follow-up4 yearsafter operation. For the whole group, 5, lo-. and I5-year survival rates were 49%. 37%,and 18%,respectively. Better survival was notedin patients with carcinoid tumor and squamous cell carcinoma. Considering 112 patients with T2 and T3 squamous cell carcinoma, 5- and IO-year survival rates for NO disease (52 patients) were 59% and 47%. for Nl disease (5 1 patients) 21% and 0%. and for N2 disease (9 patients) 4.4% and 0%. Differences between Nl and N2 disease were not statistically significant. Survival after sleeve resection is best for carcinoid tumors and squamous ceil carcinoma with negative nodes. Presence of Nl or N2 disease significantly worsens prognosis. with no lo-year survivors and no difference between Nl and N2 status.

body C219 (S. E. L. Mirski et al., Cancer Res., 47: 2594, 1987). In the present study, we have used the polymemse chain reaction to verify that H69AR cells do not overexpress P-glycoprotein. Further, transport studies with radiolabeled daunomycin, VP-16, and vinblastine demon- strate that differences in net drug accumulation or efflux are not part of the resistance phenotype of H69AR cells. To determine if H69 and H69AR cells differ in their susceptibility to drug-induced DNA dam- age, DNA single-strand breaks (SSB) generated by VP-16 and Adri- amycin were measured using the alkaline filter elution assay. Readily detectable SSB were produced in intact H69 cells by 5 pM VP-16, but 100 PM drug was required to cause similar damage in H69AR cells. H69AR cells were also resistant to SSB induction by Adriamycin. The formation of SSB by VP-16 was similarly reduced in isolated H69AR nuclei, indicating that resistance to this drug resides, at least in part, in the nucleus. No significant differences were observed in the rate or extent of repair of VP-16-induced DNA SSB in H69 and H69AR cells. The reduced susceptibility to drug-induced SSB may result from alterations in topoisomerase II, since less immunoreactive topoisom- erase II was found in H69AR cells compared to H69 cells. However, changes in topoisomerase II cannot explain the resistance of H69AR cells to such drugs as the Vinca alkaloids and gramicidin D, indicatmg that multiple mechanisms contribute to drug resistance in this small cell lung cancer cell line.

Ultrasonic surgical aspirator for lung resection Verazin GT, Regal A-M, Antkowiak JG, Parvez Z, Takita H. Division of Thoracic Surgery and Oncology, Roswell Park Cancer Institute, Elm andCarltonSfreets,Buffalo, NY 14263. AnnThoracSurg 1991:52: 787- 90.

The ultrasonic surgical aspirator was originally developed for neuro- surgical procedures and hepatic resections. Ultrasonic vibration at the tip of the instrument results in lysis of the parenchymal cells, leaving more resistant fibrous tissue such as blood vessels and bronchi intact and. thus, minimizing blood loss. We have studied the feasibility of applying the ultrasonic surgical aspirator for segmental and subsegmen- tal lung resection for primary and metastatic neoplasms of the lung. Over the past 5 years, 27 patients underwent segmental or limited lung resection using the ultrasonic surgical aspirator. Except for prolonged air leak in 6 patients postoperatively, no other serious morbidity was noted. We observed several advantages: (1) the ultrasonic surgical aspirator dissects out the pulmonary vessels and bronchi, allowing the surgeon to perform segmental and subsegmental resections with mini- mal blood loss, (2) it permits lung-sparing operation for centrally located tumors that would otherwise have required lobectomy, and (3) itallowsdirectvisuali~tionoflungparenchymaduringdissection,lhus assuring grossly adequate margins.

Chemotherapy

Non-P-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: Evidence for decreased susceptibility to drug- induced DNA damage and reduced levels of topoisomerase II Cole SPC, Chanda ER, Dicke FP, Gerlach JH, Mirski SEL. Cancer Research Laboratories. Queen’s University, Kingston, Ont. K7L 3N6. Cancer Res 1991;51:3345-52.

Data obtained from clinical samples suggest that non-P-glycoprotein mechanisms of multidrug resistance are likely to be important in small cell lung cancer. The H69AR cell line was derived from the H69 small cell lung cancer cell line by selection in doxorubicin (adriamycin) and does not overexpress P-glycoprotein as detected by monoclonal anti-

Teniposide and etoposide in previously untreated small-cell lung cancer: A randomized study Bork E, Ersboll J, Dombemowsky P, Bergman B, Hansen M, Hansen HH. Department of Oncology 5072, Finsen InstitutelRigshospitalet. 9 Blegdamsvej, DK-2100 Copenhagen. J Clin Oncol 1991;9:1627-31.

A randomized study comparing teniposide (VM-26) and etoposide (VP-16) was performed to investigate whether there are any differences in theactivityandtoxicityofthese twoanalogsinsmall-cell lungcancer (SCLC). Only previously untreated patienti with SCLC were included; 46 and 48 patients receiving VP-16 and VM-26, respectively, are assessable for response. There were no differences between the two groups witi respect to extent of disease, median age, and performance status (PS). The initial doses were for both compounds 70 mg/m’ inu’avenously (IV) daily for 5 days every 3 weeks. After inclusion of 25 patients in the study, the doses were increased to 80 mg/m’ for VM-26 and 90 mg/m* for VP-16 because of differences in toxicity. VM-26 caused more hematologic toxicity than VP-16 throughout the study. The overall responses (complete response [CR] plus partial response. FRI) were 65% for VP-16 and 71% for VM-26, with CR occurring in 24% and 23%. respectively, for the two compounds. Median survival was 8.5 months for VP-16-treated patients versus 11.3 months for VM- 26-meated patients (P = .58). It is concluded that both VP-16 and VM- 26 are highly active single agents in SCLC.

Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cispiatin Kasahara K. Fujiwara Y. Nishio K. Ohmori T. Sugimoto Y. Komiya K et al. Pharmacology Division, National Cancer Center Research In- stitute. Tsukijij-l-1, Chuo-ku, Tokyo 104. Cancer Res 1991;51:3237- 42.

We have established cis-diamminedichloroplatinum(I1) (cisplatin) resistanthumansmallcelllungcancercell lines,H69/CDDP,,andH69/ CDDP, toinvestigatethemechanism ofacquiredresistance tocisplatiu. H69/CDDP,, and H69/CDDP were 6- and 11 -fold resistant to cispiatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4- fold). 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2- methyl-5-pyrimidinyl)methyl]-1-(2-chlorcetiyl) -1. nitmsourea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand cross-link formations, determined by filter elution assay in H69/CDDP,, and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links