- Email: [email protected]
Cytotoxicity of a novel indoloquinone EO9 in hypoxic nonsmall cell lung cancer cell lines
168
Abstracts/
Lung
Cancer
comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio of 0.87 (I 3% reduction in the risk of death; absolute benefit of 4% at two years), and trials comparing supportive care with supportive care plus chemotherapy 0.73 (27% reduction in the risk ofdeath; 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size ofeffect was seen in any subgroup ofpatients. In ah but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. Conclusion - At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.
Chemotherapy in non-small cell lung cancer Thatcher
N, Ranson LM, Lee LSM, Niven R. Anderson H. CRC Deparrment Medical Oncology, Christie and Wythenshawe Hospitals. WilmslowRoad. ManchesterM209BX. AnnOncol1995;6:Suppl 1 :S8395. Background: Non-small cell lung cancer can no longer be regarded as resistant to chemotherapy, and there have recently been considerable improvements in the use of the older agents and advances in the identification of new drugs. Recent meta-analysis has also confirmed the view that chemotherapy can have small but modest survival benefits. Although in the treatment ofstage IVdisease the ctiteriaofefficacy have concentrated on tumour response rates more recently it has become obvious that these patients can also benefit in terms of improved symptom control. Recent advances: For patients with locally advanced stage III disease there have been important developments indicating the benefitofcombinedmodalitytrea~entwithchemotherapyandthoracic irradiation. Furthermore, the use ofneoadjuvant chemotherapy indicates that resection is possible in about half the patients, and on pathological examination of 15%-20% ofthe resected specimens there is no evidence of residual tumour. These results justify an increase in the use of systemic chemotherapy in this disease.
Is there a role for chemotherapy of non-small cell lung cancer? Hansen HH. Department University
of Oncology, The Finsen Center, National DK-2100 Copenhagen. AM Oncol 1995;6:Suppl
Hospital,
l:S79-82. This paper reviews the results of individual studies and metaanalyses ofchemotherapy of non-small cell lung cancer. The published results from studies of chemotherapy as part of a combined modality therapy which have been carried out in the last decade are conflicting. Some show a statistically superior survival for the group receiving chemotherapy compared with a best supportive care group, while the others show no advantage. The differences, however, are small. Metaanalysisofdatafrompublishedrandomizedtrialshasbeenusedbysome authors to assess combination chemotherapy compared to supportive or palliative treatment of patients of non-resectable non-small cell lung cancer. In some of the randomized trials and meta-analyses results, a statistically significant effect on survival parameters following chemotherapy against non-small cell lung cancer is shown. The clinical significance of these observations is questionable and the results from larger ongoing trials must be awaited before chemotherapy is used routinely in the treatment of advanced NSCLC.
New drugs in the treatment of non-small cell lung cancer Steward
WP, Dunlop
University,
1995;6:Suppl
82-84
Barrie
l:S49-54.
DJ. NCIC Street,
Clinical Kingston,
Trials Ont. K7L
Group. Queen’s 3N6. Ann Oncol
14 (19%)
149-179
Non-small cell lungcanceraccountsfor75%ofall lungtumours,and onlyabout lO%ofpatientswill remainalive 5 yearsafterdiagnosis. Few cytotoxic drugs currently registered produce more than a 15% response rate as a single agent or 30%-35% in combination, with only modest survival benefits. New cytotoxic drugs entering phase II and III studies. however, appear to have more than 20% activity against this disease. They include the taxanes (tax01 and taxotere), camptothecin anaIogues (CPT- I I and topotecan), anti-metabolites (edatrexate and gemcitabine) and the vinca alkaloid, navelbine. Tax01 produces response rates of about 25% in previously untreated patients and is currently undergoing trials at higher doses in combination with cisplatin and granulocyte colony-stimulating factor. Taxotere produces response rates of 33% in previously untreated patients and 2 1% in patients previously refractory to platinum-containing regimens. The camptothecin analogues, which are inhibitors of topoisomerase I, may produce response rates of up to 41% in previously untreated patients, but these results have varied considerably between different trials (response rates as low as 13.5% have been reported for topotecan). A phase II study with edatrexate produced a response rate of 32%, but subsequent trials using combination chemotherapy including this agent have been disappointing. The activity of gemcitabine as a single agent is 20%-25%. Three ongoing phase II studies combining cisplatin and gemcitabine have shown response rates of up to 50%. Gemcitabine has minimal subjective toxicity. Navelbine produces response rates of 22%-33% as a single agent and up to 65% in combination. These new cytotoxic agents with significant activity in non-small cell lung cancer provide exciting potential for developing novel combination regimens in the advanced setting and as neoadjuvant and adjuvant therapy.
Cytotoxicity of a novel indoloquinone small cell lung cancer cell lines
E09 in hypoxic non-
Bando T, Kasahara K, Shibata K, Numata Y, Heki U, Shims&i
H et aI.
Third Dept. of Internal Medicine, Kanazawa Universiry. School of Medicine. 13-I Takara-machi, Kanazawa 920. Int J OncoI 1995;7:789-
93. 3-Hydroxymethyl-5-ariridinyl-l-methyl-[lH-indole-4,7-di one]prop-beta-en-alpha -01 (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and sructuralIy related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of E09 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to E09 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/ MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC,, value of PC-9 againstEO9 wassignificantlyincreasedbyco-incubationwithdicumarol under oxic conditions. E09 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempo1 under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of E09 under hypoxic conditions and EG9 may be more active against oxygendeficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity.
Evaluationoftheresponsetochemotherapyinpatientsaffected with small cell lung cancer using discrimlnant analysis: A preliminary report Paone G, De Angelis G, PaIIottaG,
Giannarelli
D, Bisetti A, Pigorini F
Abstracts/
Lung
Cancer
comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio of 0.87 (I 3% reduction in the risk of death; absolute benefit of 4% at two years), and trials comparing supportive care with supportive care plus chemotherapy 0.73 (27% reduction in the risk ofdeath; 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size ofeffect was seen in any subgroup ofpatients. In ah but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. Conclusion - At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.
Chemotherapy in non-small cell lung cancer Thatcher
N, Ranson LM, Lee LSM, Niven R. Anderson H. CRC Deparrment Medical Oncology, Christie and Wythenshawe Hospitals. WilmslowRoad. ManchesterM209BX. AnnOncol1995;6:Suppl 1 :S8395. Background: Non-small cell lung cancer can no longer be regarded as resistant to chemotherapy, and there have recently been considerable improvements in the use of the older agents and advances in the identification of new drugs. Recent meta-analysis has also confirmed the view that chemotherapy can have small but modest survival benefits. Although in the treatment ofstage IVdisease the ctiteriaofefficacy have concentrated on tumour response rates more recently it has become obvious that these patients can also benefit in terms of improved symptom control. Recent advances: For patients with locally advanced stage III disease there have been important developments indicating the benefitofcombinedmodalitytrea~entwithchemotherapyandthoracic irradiation. Furthermore, the use ofneoadjuvant chemotherapy indicates that resection is possible in about half the patients, and on pathological examination of 15%-20% ofthe resected specimens there is no evidence of residual tumour. These results justify an increase in the use of systemic chemotherapy in this disease.
Is there a role for chemotherapy of non-small cell lung cancer? Hansen HH. Department University
of Oncology, The Finsen Center, National DK-2100 Copenhagen. AM Oncol 1995;6:Suppl
Hospital,
l:S79-82. This paper reviews the results of individual studies and metaanalyses ofchemotherapy of non-small cell lung cancer. The published results from studies of chemotherapy as part of a combined modality therapy which have been carried out in the last decade are conflicting. Some show a statistically superior survival for the group receiving chemotherapy compared with a best supportive care group, while the others show no advantage. The differences, however, are small. Metaanalysisofdatafrompublishedrandomizedtrialshasbeenusedbysome authors to assess combination chemotherapy compared to supportive or palliative treatment of patients of non-resectable non-small cell lung cancer. In some of the randomized trials and meta-analyses results, a statistically significant effect on survival parameters following chemotherapy against non-small cell lung cancer is shown. The clinical significance of these observations is questionable and the results from larger ongoing trials must be awaited before chemotherapy is used routinely in the treatment of advanced NSCLC.
New drugs in the treatment of non-small cell lung cancer Steward
WP, Dunlop
University,
1995;6:Suppl
82-84
Barrie
l:S49-54.
DJ. NCIC Street,
Clinical Kingston,
Trials Ont. K7L
Group. Queen’s 3N6. Ann Oncol
14 (19%)
149-179
Non-small cell lungcanceraccountsfor75%ofall lungtumours,and onlyabout lO%ofpatientswill remainalive 5 yearsafterdiagnosis. Few cytotoxic drugs currently registered produce more than a 15% response rate as a single agent or 30%-35% in combination, with only modest survival benefits. New cytotoxic drugs entering phase II and III studies. however, appear to have more than 20% activity against this disease. They include the taxanes (tax01 and taxotere), camptothecin anaIogues (CPT- I I and topotecan), anti-metabolites (edatrexate and gemcitabine) and the vinca alkaloid, navelbine. Tax01 produces response rates of about 25% in previously untreated patients and is currently undergoing trials at higher doses in combination with cisplatin and granulocyte colony-stimulating factor. Taxotere produces response rates of 33% in previously untreated patients and 2 1% in patients previously refractory to platinum-containing regimens. The camptothecin analogues, which are inhibitors of topoisomerase I, may produce response rates of up to 41% in previously untreated patients, but these results have varied considerably between different trials (response rates as low as 13.5% have been reported for topotecan). A phase II study with edatrexate produced a response rate of 32%, but subsequent trials using combination chemotherapy including this agent have been disappointing. The activity of gemcitabine as a single agent is 20%-25%. Three ongoing phase II studies combining cisplatin and gemcitabine have shown response rates of up to 50%. Gemcitabine has minimal subjective toxicity. Navelbine produces response rates of 22%-33% as a single agent and up to 65% in combination. These new cytotoxic agents with significant activity in non-small cell lung cancer provide exciting potential for developing novel combination regimens in the advanced setting and as neoadjuvant and adjuvant therapy.
Cytotoxicity of a novel indoloquinone small cell lung cancer cell lines
E09 in hypoxic non-
Bando T, Kasahara K, Shibata K, Numata Y, Heki U, Shims&i
H et aI.
Third Dept. of Internal Medicine, Kanazawa Universiry. School of Medicine. 13-I Takara-machi, Kanazawa 920. Int J OncoI 1995;7:789-
93. 3-Hydroxymethyl-5-ariridinyl-l-methyl-[lH-indole-4,7-di one]prop-beta-en-alpha -01 (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and sructuralIy related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of E09 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to E09 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/ MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC,, value of PC-9 againstEO9 wassignificantlyincreasedbyco-incubationwithdicumarol under oxic conditions. E09 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempo1 under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of E09 under hypoxic conditions and EG9 may be more active against oxygendeficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity.
Evaluationoftheresponsetochemotherapyinpatientsaffected with small cell lung cancer using discrimlnant analysis: A preliminary report Paone G, De Angelis G, PaIIottaG,
Giannarelli
D, Bisetti A, Pigorini F