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Chemotherapy in adenocarcinoma of the lung
204
Chemotherapy
in adenocarcinoma
of the lung
Sorensen JB, Hansen HH. Department of Oncology, The Finsen InstifufeiRigshospi~&f, 9 Blegdamsvej. 2100 Copenhagen. Cancer SW 1989;8:671-9.
Adenocarcinoma of the lung (ACL) attracts increasing attention because of the fast rising incidence. Systemic chemotherapy with cytostatic agents has been widely used for patients with inoperable ACL, but a standard treatment has not yet been defined. A review of the literature revealed that the highest response rates observed for single agents and combination chemotherapy in ACL in randomized studies were 22% and 38%, respectively, while the longest median survivals were 35 weeks and 34 weeks. Independent prognostic factors for survival in ACL patients were performance status, prior non-radical resection, liver metastases, white blood cell count and serum values of lactate dehydrogenase and aspartic aminotransaminase. Using logistic regression analysis, the only significant predictor of response was measurable disease parameter, while 26 other variables were not significant. Response to chemotherapy was not a major prognostic factor for survival, probably because of the low rate of complete responses (4%). Chemotherapy in ACL remains experimental and the prognosis for these patients is poor. High priority should therefore be given to the identification of new agents or combination regimens with appreciable activity. The knowledge of prognostic factors should be. used for optimal design of trials and interpretation of the results. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human lung cancer cell lines Tsai C-M, Gazdar AF, Allegra C, Perng R-P, Kramer BS. Chest Department, Vererans General Hospiml, Taipei 11217. Int J Cancer
1990;46:101-5. Reduced folates have been shown to increase the cytotoxicity of 5fluorouracil (FUra) by stabilizing the fluorodexoyuridine monophosphatexbymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium calorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-lluomdeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 pM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in theonly remaining line. ThedifferentialeffectsofLVonthecytotoxicity of FUra vs FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported Cram our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines. A study of human small-cell lung carcinoma (LSCLC) cell lineswith different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance
Hospers GAP. Meijer C. De Leij L. Uges DRA, Mulder NH, De Vries EGE. Deparmxnl of Interno Medicine. University Hospiral. Oosrersingel59,9713 EZ Groningen. Int 1 Cancer 1990;46:138-44. The cisplatin(CDDP)-resistant cell line GLC,-CDDP shows a variety of differences from the parent line GLC,. The aim of this study was to determine which of the observed changes correlated with the degree of resistance and was therefore relevant to the phenomenon of CDDP resistance. For these experiments we used cells of the sensitive hSCLC cell lineGLC,andthein vitro-acquiredCDDP-resistantsublinesGLC,CDDP3 and GLC,-CDDPI I, with a resistance factor (RF) of 3 and 11 respectively for CDDP and of I .8 and 7.4 respectively for carboplatin. Carboplatin was used, in addition to CDDP in seeking relevant mechanisms.NoconsistencywasfoundbctweentheRFandthegrowibpattem or antigen expression, cellular volume, doubling time, cellular or nuclear platinum (Pt) content or the level of Pt-non-histone chromatin protein (NHCP) binding. A correlation was found between the RF and the level of glutathione (GSH), and a trend was found for the level of PtDNA binding, Pt-GG adduct content and the amount of interstrand cross-links (UC). These changes might therefore be relevant for the development of resistance. These findings are compatible with a GSH-
induced reduction of the amount of reactive Pt in the resistant cell, resulting in a lower net platination and toxic P&DNA adduct formation. Chemosensitivity testing of human lung cancer tissues using the succinate dehydrogenase inhibition test Mitsudomi T, Kaneko S, Tateishi M et al. Deportment ofSurgery II, Focully of Medicine, Kyushu University. 3-I-I Maidashi, Higashi-ku, Fukuoka 812. Anticancer Res 1990;10:987-90.
We examined the chemosensitivity of 57 primary lung cancer specimens to 9 antitumor drugs, using the succinate dehydrogenase inhibition (SDI) test. Average succinate dehydrogenase (SD) activity was reduced to less than 50% by cis-diaminedichloroplatinum (II) (DDP), cyclophosphamide (CPA), carboquone (CQ), mitomycin C (MMC) and adriamycin (ADM). The lung cancer cells were relatively resistant to pepleomycin (PEP), 5-fluomuracil(5FU), vincristine (VCR) and vindesine (VDS). Small cell lung cancers, or early stage lung cancers, tended to be more sensitive to these antitumor drugs. However, differences in sensitivity with respect to either histology, staging or degree of differentiation were not statistically significant. Correlation of SD activity between 2 drugs was high among those which inhibit DNA synthesis (DDP, CPA, CQ or MMC), or between VCR and VDS (inhibitor ofmitosis), however, the correlation between VDS andCPA, CQ or DDP was weak. The SD1 test is a simple in vitro method readily available to aid in selecting drugs to treat patients with lung cancer. A randomized comparison of cisplatin-vindesine and cisplatinetoposide for the treatment of previously untreated, advanced non-
small ceil lung cancer Niiranen A, Niitamo-Korhonen S, Holsti P, Holsti LR. Pulmonary Medicine and OncologyDeparonenl. Helsinki UniversityCenrral Hospital. Helsinki. Cancer J 1990;3:219-23. 136 patients with advanced non-small cell lung cancer were randomized for a clinical trial comparing cisplatin (p) (90 mg/m2) plus vindesine (VDS) (3 mg/mz) with cisplatin plus etoposide (VP-16) (50 mg/m*). 78/136 patients received two or more chemotherapy cycles. There were 14/72 objective responses (2 complete. responses, 12 partial responses) in the P-VDS group as compared with 6/64 (partial re.sponses) in the P-VP-16 group. However, there were no significant differences in the duration of response (187 days vs. 217 days respectively) or in survival. The median survival time (MS) was 181 days in the P-VDS group and 166 days in the P-VP-16 group. The MS for the responding patients was 406 days in the P-VDS gmup and 344 days in the P-VP- 16 group; the corresponding figures for the non-responders were 181 days and 166 days respectively. The one-year survival rate. was 3 1% in the P-VDS group and 29% in the P-VP- I6 group. The twoyear survival rates were 3% and 8% respectively. A better Kamofsky performance status was a positive prognostic sign. 58/136 patients did not complete two chemotherapy cycles, mostly due to poor chemotberapy tolerance combined with a heavy tumour burden and progressive disease. Our study showed no statistically significant improvement of survival rate after the P-VDS regimen compared with the P-VP-16 regimen. The P-VP-16 was slightly better tolerated than the P-VDS regimen. Mitomycin, ifosfamide, and mesna in the treatment of lung cancer Dorr RT. Arizona Cancer Center. University of Arizona, College of Medicine, 1515 N Campbell Ave. Tucson, AZ 85724. Semin Oncol
1990:17:Suppl7:2-5. Observations have been made of the multiple-drug resistance phenomenon in mitomycin-exposed cells in vitro. Collateral resistance to antbracyclines and Vinca alkaloids was demonstrated in mitomycin carbon-treated I-12lOcells in vitro. However, because it has also been found that this resistance can be reversed with agents such as verapamil and progestogens, it may be possible to effect a similar reversal in viva. A study is currently being performed in patients with colorectal cancer, in which the potential for reversal is being tested. The pharmacokinetics of ifosfamide result in high cytotoxic specificity which. along with its therapeutic range, makes it a particularly active agent in the treatment of non-small cell lung cancer. Its urotoxicity is effectively controlled by the coadministmtion of mesna, a uropmtective agent.
Chemotherapy
in adenocarcinoma
of the lung
Sorensen JB, Hansen HH. Department of Oncology, The Finsen InstifufeiRigshospi~&f, 9 Blegdamsvej. 2100 Copenhagen. Cancer SW 1989;8:671-9.
Adenocarcinoma of the lung (ACL) attracts increasing attention because of the fast rising incidence. Systemic chemotherapy with cytostatic agents has been widely used for patients with inoperable ACL, but a standard treatment has not yet been defined. A review of the literature revealed that the highest response rates observed for single agents and combination chemotherapy in ACL in randomized studies were 22% and 38%, respectively, while the longest median survivals were 35 weeks and 34 weeks. Independent prognostic factors for survival in ACL patients were performance status, prior non-radical resection, liver metastases, white blood cell count and serum values of lactate dehydrogenase and aspartic aminotransaminase. Using logistic regression analysis, the only significant predictor of response was measurable disease parameter, while 26 other variables were not significant. Response to chemotherapy was not a major prognostic factor for survival, probably because of the low rate of complete responses (4%). Chemotherapy in ACL remains experimental and the prognosis for these patients is poor. High priority should therefore be given to the identification of new agents or combination regimens with appreciable activity. The knowledge of prognostic factors should be. used for optimal design of trials and interpretation of the results. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human lung cancer cell lines Tsai C-M, Gazdar AF, Allegra C, Perng R-P, Kramer BS. Chest Department, Vererans General Hospiml, Taipei 11217. Int J Cancer
1990;46:101-5. Reduced folates have been shown to increase the cytotoxicity of 5fluorouracil (FUra) by stabilizing the fluorodexoyuridine monophosphatexbymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium calorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-lluomdeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 pM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in theonly remaining line. ThedifferentialeffectsofLVonthecytotoxicity of FUra vs FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported Cram our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines. A study of human small-cell lung carcinoma (LSCLC) cell lineswith different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance
Hospers GAP. Meijer C. De Leij L. Uges DRA, Mulder NH, De Vries EGE. Deparmxnl of Interno Medicine. University Hospiral. Oosrersingel59,9713 EZ Groningen. Int 1 Cancer 1990;46:138-44. The cisplatin(CDDP)-resistant cell line GLC,-CDDP shows a variety of differences from the parent line GLC,. The aim of this study was to determine which of the observed changes correlated with the degree of resistance and was therefore relevant to the phenomenon of CDDP resistance. For these experiments we used cells of the sensitive hSCLC cell lineGLC,andthein vitro-acquiredCDDP-resistantsublinesGLC,CDDP3 and GLC,-CDDPI I, with a resistance factor (RF) of 3 and 11 respectively for CDDP and of I .8 and 7.4 respectively for carboplatin. Carboplatin was used, in addition to CDDP in seeking relevant mechanisms.NoconsistencywasfoundbctweentheRFandthegrowibpattem or antigen expression, cellular volume, doubling time, cellular or nuclear platinum (Pt) content or the level of Pt-non-histone chromatin protein (NHCP) binding. A correlation was found between the RF and the level of glutathione (GSH), and a trend was found for the level of PtDNA binding, Pt-GG adduct content and the amount of interstrand cross-links (UC). These changes might therefore be relevant for the development of resistance. These findings are compatible with a GSH-
induced reduction of the amount of reactive Pt in the resistant cell, resulting in a lower net platination and toxic P&DNA adduct formation. Chemosensitivity testing of human lung cancer tissues using the succinate dehydrogenase inhibition test Mitsudomi T, Kaneko S, Tateishi M et al. Deportment ofSurgery II, Focully of Medicine, Kyushu University. 3-I-I Maidashi, Higashi-ku, Fukuoka 812. Anticancer Res 1990;10:987-90.
We examined the chemosensitivity of 57 primary lung cancer specimens to 9 antitumor drugs, using the succinate dehydrogenase inhibition (SDI) test. Average succinate dehydrogenase (SD) activity was reduced to less than 50% by cis-diaminedichloroplatinum (II) (DDP), cyclophosphamide (CPA), carboquone (CQ), mitomycin C (MMC) and adriamycin (ADM). The lung cancer cells were relatively resistant to pepleomycin (PEP), 5-fluomuracil(5FU), vincristine (VCR) and vindesine (VDS). Small cell lung cancers, or early stage lung cancers, tended to be more sensitive to these antitumor drugs. However, differences in sensitivity with respect to either histology, staging or degree of differentiation were not statistically significant. Correlation of SD activity between 2 drugs was high among those which inhibit DNA synthesis (DDP, CPA, CQ or MMC), or between VCR and VDS (inhibitor ofmitosis), however, the correlation between VDS andCPA, CQ or DDP was weak. The SD1 test is a simple in vitro method readily available to aid in selecting drugs to treat patients with lung cancer. A randomized comparison of cisplatin-vindesine and cisplatinetoposide for the treatment of previously untreated, advanced non-
small ceil lung cancer Niiranen A, Niitamo-Korhonen S, Holsti P, Holsti LR. Pulmonary Medicine and OncologyDeparonenl. Helsinki UniversityCenrral Hospital. Helsinki. Cancer J 1990;3:219-23. 136 patients with advanced non-small cell lung cancer were randomized for a clinical trial comparing cisplatin (p) (90 mg/m2) plus vindesine (VDS) (3 mg/mz) with cisplatin plus etoposide (VP-16) (50 mg/m*). 78/136 patients received two or more chemotherapy cycles. There were 14/72 objective responses (2 complete. responses, 12 partial responses) in the P-VDS group as compared with 6/64 (partial re.sponses) in the P-VP-16 group. However, there were no significant differences in the duration of response (187 days vs. 217 days respectively) or in survival. The median survival time (MS) was 181 days in the P-VDS group and 166 days in the P-VP-16 group. The MS for the responding patients was 406 days in the P-VDS gmup and 344 days in the P-VP- 16 group; the corresponding figures for the non-responders were 181 days and 166 days respectively. The one-year survival rate. was 3 1% in the P-VDS group and 29% in the P-VP- I6 group. The twoyear survival rates were 3% and 8% respectively. A better Kamofsky performance status was a positive prognostic sign. 58/136 patients did not complete two chemotherapy cycles, mostly due to poor chemotberapy tolerance combined with a heavy tumour burden and progressive disease. Our study showed no statistically significant improvement of survival rate after the P-VDS regimen compared with the P-VP-16 regimen. The P-VP-16 was slightly better tolerated than the P-VDS regimen. Mitomycin, ifosfamide, and mesna in the treatment of lung cancer Dorr RT. Arizona Cancer Center. University of Arizona, College of Medicine, 1515 N Campbell Ave. Tucson, AZ 85724. Semin Oncol
1990:17:Suppl7:2-5. Observations have been made of the multiple-drug resistance phenomenon in mitomycin-exposed cells in vitro. Collateral resistance to antbracyclines and Vinca alkaloids was demonstrated in mitomycin carbon-treated I-12lOcells in vitro. However, because it has also been found that this resistance can be reversed with agents such as verapamil and progestogens, it may be possible to effect a similar reversal in viva. A study is currently being performed in patients with colorectal cancer, in which the potential for reversal is being tested. The pharmacokinetics of ifosfamide result in high cytotoxic specificity which. along with its therapeutic range, makes it a particularly active agent in the treatment of non-small cell lung cancer. Its urotoxicity is effectively controlled by the coadministmtion of mesna, a uropmtective agent.