scholarly journals Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Huanyu He ◽  
Xinmao Song ◽  
Zuozhang Yang ◽  
Yuchi Mao ◽  
Kunming Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Stereotactic Body Radiotherapy ◽  
Clinical Stage ◽  
Resistant Cell ◽  
Antitumor Effects ◽  
Large Tumor ◽  
Advanced Clinical Stage ◽  
Potential Strategy

Abstract Stereotactic body radiotherapy (SBRT) has emerged as a standard treatment for non-small-cell lung cancer. However, its therapeutic advantages are limited with the development of SBRT resistance. The SBRT-resistant cell lines (A549/IR and H1975/IR) were established after exposure with hypofractionated irradiation. The differential lncRNAs were screened by microarray assay, then the expression was detected in LUAD tumor tissues and cell lines by qPCR. The influence on radiation response was assessed via in vitro and in vivo assays, and autophagy levels were evaluated by western blot and transmission electron microscopy. Bioinformatics prediction and rescue experiments were used to identify the pathways underlying SBRT resistance. High expression of KCNQ1OT1 was identified in LUAD SBRT-resistant cells and tissues, positively associated with a large tumor, advanced clinical stage, and a lower response rate to concurrent therapy. KCNQ1OT1 depletion significantly resensitized A549/IR and H1975/IR cells to radiation by inhibiting autophagy, which could be attenuated by miR-372-3p knockdown. Furthermore, autophagy-related 5 (ATG5) and autophagy-related 12 (ATG12) were confirmed as direct targets of miR-372-3p. Restoration of either ATG5 or ATG12 abrogated miR-372-3p-mediated autophagy inhibition and radiosensitivity. Our data describe that KCNQ1OT1 is responsible for SBRT resistance in LUAD through induction of ATG5- and ATG12-dependent autophagy via sponging miR-372-3p, which would be a potential strategy to enhance the antitumor effects of radiotherapy in LUAD.

scholarly journals Circular RNA circ_001422 Promotes Progression and Metastasis of Osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt Axis

2021 ◽  
Author(s):  
Bingsheng Yang ◽  
Lutao Li ◽  
Ge Tong ◽  
Zhirui Zeng ◽  
Jianye Tan ◽  
...  
Keyword(s):  
Cell Lines ◽  
Clinical Stage ◽  
Distant Metastases ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Advanced Clinical Stage ◽  
Bioinformatics Databases ◽  
Rna Immunoprecipitation

Abstract BackgroundCircular RNAs (circRNAs) are involved in diverse processes that drive cancer development. Nevertheless, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied.MethodsBioinformatics analysis and high-throughput RNA sequencing tools were employed to determine differentially expressed circRNAs between OS and adjacent healthy tissues. The expression levels of circ_001422 in clinical specimens and cell lines were measured using qRT-PCR. A total of 55 OS patients were recruited to analyze the association of circ_001422 expression with clinicopathologic features. Loss- and gain-of-function tests were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescent in situ hybridization, bioinformatics databases, RNA pull-down assay, dual-luciferase reporter assay, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNAs regulatory network dominated by circ_001422.ResultsWe characterized a novel and abundant circRNA, circ_001422, which promoted the progression of OS. Circ_001422 expression was dramatically higher in OS cell lines and tissues relative to normal samples. Increased circ_001422 correlated with more advanced clinical stage, larger tumor size, more distant metastases and poorer overall survival of OS patients. Knockdown of circ_001422 markedly repressed proliferation and metastasis and promoted apoptosis of OS cells in vivo and in vitro, whereas overexpression of circ_001422 exerted an opposite effect. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated the expression of FGF2 while also initiating the PI3K/Akt signaling pathway. These events enhanced the malignant characteristics of OS cells.ConclusionsCirc_001422 accelerates OS tumorigenesis and metastasis through modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 could be therapeutically targeted to treat OS patients.

scholarly journals Circular RNA circ_001422 promotes the progression and metastasis of osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Bingsheng Yang ◽  
Lutao Li ◽  
Ge Tong ◽  
Zhirui Zeng ◽  
Jianye Tan ◽  
...  
Keyword(s):  
Cell Lines ◽  
Clinical Stage ◽  
Distant Metastases ◽  
Bioinformatic Analysis ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Advanced Clinical Stage

Abstract Background Circular RNAs (circRNAs) are involved in diverse processes that drive cancer development. However, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied. Methods Bioinformatic analysis and high-throughput RNA sequencing tools were employed to identify differentially expressed circRNAs between OS and adjacent noncancerous tissues. The expression level of circ_001422 in clinical specimens and cell lines was measured using qRT-PCR. The association of circ_001422 expression with the clinicopathologic features of 55 recruited patients with OS was analyzed. Loss- and gain-of-function experiments were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescence in situ hybridization, bioinformatics database analysis, RNA pulldown assays, dual-luciferase reporter assays, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNA regulatory network controlled by circ_001422. Results We characterized a novel and abundant circRNA, circ_001422, that promoted OS progression. Circ_001422 expression was dramatically increased in OS cell lines and tissues compared with noncancerous samples. Higher circ_001422 expression correlated with more advanced clinical stage, larger tumor size, higher incidence of distant metastases and poorer overall survival in OS patients. Circ_001422 knockdown markedly repressed the proliferation and metastasis and promoted the apoptosis of OS cells in vivo and in vitro, whereas circ_001422 overexpression exerted the opposite effects. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated FGF2 expression while also initiating PI3K/Akt signaling. These events enhanced the malignant characteristics of OS cells. Conclusions Circ_001422 accelerates OS tumorigenesis and metastasis by modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 can be therapeutically targeted to treat OS.

scholarly journals Imidazole Analogs of Vascular-Disrupting Combretastatin A-4 with Pleiotropic Efficacy against Resistant Colorectal Cancer Models

2021 ◽  
Vol 22 (23) ◽  
pp. 13082
Author(s):  
Franziska Reipsch ◽  
Bernhard Biersack ◽  
Henrike Lucas ◽  
Rainer Schobert ◽  
Thomas Mueller
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Antitumor Effects ◽  
Metastasis Model ◽  
Main Representative ◽  
Vascular Disrupting

Specific targeting of the tumoral vasculature by vascular-disrupting agents (VDA), of which combretastatin A-4 (CA-4) is a main representative, has been considered a new therapeutic strategy against multidrug-resistant tumors. In addition, CA-4 and analogs are tubulin-targeting agents and can exert direct antitumor effects by different mechanisms. Herein, we analyzed a series of synthetic CA-4 analogs featuring N-methylimidazole-bridged Z-alkenes with different halo- or amino-substituted aryl rings in vitro and in vivo, focusing on models of colorectal cancer. Combined in vitro/in vivo structure–activity relationship studies using cell lines and xenograft tumors susceptible to VDA-induced vascular damage demonstrated a clear association of cytotoxic and vascular-disrupting activity with the ability to inhibit tubulin polymerization, which was determined by specific substitution constellations. The most active compounds were tested in an extended panel of colorectal cancer (CRC) cell lines and showed activity in CA-4-resistant and chemotherapy-resistant cell lines. The bromo derivative brimamin was then compared with the known fosbretabulin (CA-4P) by activity tests on DLD-1- (multidrug-resistant) and HT29- (CA-4-resistant) derived xenograft tumors. Treatment did not induce pronounced vascular-disrupting effects in these tumors. Histological analyses revealed distinct tumor substructures and vessel compositions of DLD-1/HT29 tumors, which clearly differed from the tumor models susceptible to VDA treatment. Even so, brimamin effectively retarded the growth of DLD-1 tumors, overcoming their resistance to standard treatment, and it inhibited the outgrowth of disseminated HT29 tumor cells in an experimental metastasis model. In conclusion, combretastatin analogous N-methylimidazoles proved capable of inducing vascular-disrupting effects, comparable to those of CA-4P. In addition, they showed antitumor activities in models of drug-resistant colorectal cancer, independent of vascular-disrupting effects.

scholarly journals Stable Transduction of the Interleukin-2 Gene Into Human Natural Killer Cell Lines and Their Phenotypic and Functional Characterization In Vitro and In Vivo

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3850-3861 ◽  
Author(s):  
Shigeki Nagashima ◽  
Robbie Mailliard ◽  
Yoshiro Kashii ◽  
Torsten E. Reichert ◽  
Ronald B. Herberman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Lines ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Human Natural Killer Cell ◽  
Antitumor Effects ◽  
Packaging Cell Line

Abstract A variety of strategies have been attempted in the past to stably transduce natural killer (NK) cells with cytokine or other cellular genes. Here, we demonstrate the successful delivery of the interleukin-2 (IL-2) gene into two human NK cell lines, IL-2–dependent NK-92 and IL-2–independent YT, by retroviral transduction. An MuLV-based retroviral vector expressing human IL-2 andneor markers from a polycistronic message was constructed and transduced into a CRIP packaging cell line. By coincubation of NK cells with monolayers of CRIP cells or by using retrovirus-containing supernatants in a flow-through method, 10% to 20% of NK cells were stably transduced. Upon selection in the presence of increasing G418 concentrations, transduced NK cells were able to proliferate independently of IL-2 for more than 5 months and to secrete up to 5.5 ng/106 cells/24 h of IL-2. IL-2 gene-transduced NK-92 cells had an in vitro cytotoxicity against tumor targets that was significantly higher than that of parental cells and secreted interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) in addition to IL-2. Moreover, the in vivo antitumor activity of IL-2 gene-transduced NK-92 cells against established 3-day liver metastases in mice was greater than that of parental nontransduced NK cells. Stable expression of the IL-2 transgene in NK cells improved their therapeutic potential in tumor-bearing hosts. Thus, transduced NK cells secreted sufficient quantities of bioactive IL-2 to proliferate in vitro and mediated the antitumor effects both in vitro and in vivo in the absence of exogenous IL-2. These results suggest that genetic modification of NK cells ex vivo could be useful for clinical cancer therapy in the future.

Cytotoxic Effects of 24/R,25-Dihydroxycholecalciferol on the Proliferation of Various Tumor Cell Lines in vitro and Its Antitumor Effects in vivo

Oncology ◽  
1988 ◽  
Vol 45 (3) ◽  
pp. 206-209 ◽  
Author(s):  
Yuji Maeda ◽  
Tohru Hirai ◽  
Hideyuki Yamato ◽  
Noriko Kobori ◽  
Ken-ichi Matsunaga ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Tumor Cell Lines ◽  
Antitumor Effects ◽  
Cytotoxic Effects

New targeted anti CDK4/6 peptide MM-D37K.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13545-e13545 ◽  
Author(s):  
Vladimir Konstantinovich Bozhenko ◽  
Tatyana Michailovna Kulinich ◽  
Elena Aleksandrovna Kudinova ◽  
Andrey Boldyrev ◽  
Vladimir Alekseevich Solodkij
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Full Range ◽  
Mrna Level ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Antitumor Effects ◽  
Mcf 7

e13545 Background: MM-D37K is a synthetic peptide which consists of p16INK4a-specific inhibitor of complex cyclin D- CDK4 and CDK6 and cell penetrating peptide (CPP) – Antp (Penetratin). We investigated in vitro and in vivo cytotoxic, cytostatic and antitumor activity of MM-D37K. The level of cyclin A, Ki67,bax, bcl-2 and pRb phosphorylation was investigated. Full range of Toxicology tests and Pharmacokinetics experiments in mice, rats and rabbits were performed. Methods: Different cell lines (Jurcat, Raji, A549, MCF-7, Hct-116, Ht-29, HEK293) were incubated with 0.1-100 mM MM-D37K for 24-48 hrs. Proliferation (MTT), DNA-content, cell cycle (flow cytometry) and mRNA level of appropriate proteins (RT PCR) were investigated. In vivo experiments were conducted on xenograft model of HCT116, A-549 at concentration 5 and 10 mg/kg of MM-D37K. Toxicology experiments were made under RF Law and included 3 types of animals. LC-MS MMD37K method of detection in plasma was developed. Results: MM-D37K prevented pRb phosphorilation and proliferation activation in all investigated cell lines. Cell cycle was blocked in G1 phase. Cytostatic effect did not depend on p16 mutation or expression. MM-D37K induced apoptosis in 20-82% of investigated cells at 40 mM with lowest level for MCF-7. LD10 for rats was 100 mg/kg and no deaths were registered for rabbits (highest dose was 50 mg/kg). Concentration of MMD-37K in plasma after 2 min and bolus i.v. injection in dose 10 mg/kg was 72.16±5.64 mcg/ml. Concentration decreased in two phases. 1st – t1/2 = 2.39±0.39 min and for 2nd t1/2=2.39±0.39 hr. Antitumor effects in xenograft model were 53% for A-549 and 67% for HCT116. Conclusions: Our results proved cytotoxic, cytostatic and antitumor effects of MM-D37K in investigated cell lines in vitro and in vivo. Toxicological and pharmacokinetics results allow us recommend for I/IIa Phase clinical trial. (Support: MetaMax Ltd., RFFI, Minpromtorg RF.)

scholarly journals Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Tetsuya Yamada ◽  
Shohei Tsuji ◽  
Shinsuke Nakamura ◽  
Yusuke Egashira ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dna Methyltransferase ◽  
Antitumor Effect ◽  
Metabotropic Glutamate Receptor ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase

OBJECTIVEGlutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo.METHODSThree GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells.RESULTSRiluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05).CONCLUSIONSRiluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

scholarly journals ALT Neuroblastoma Chemoresistance due to ATM Activation by Telomere Dysfunction is Reversible with the ATM Inhibitor AZD0156

2021 ◽  
Author(s):  
Balakrishna Koneru ◽  
Ahsan Farooqi ◽  
Thinhh H. Nguyen ◽  
Wan Hsi Chen ◽  
Ashly Hindle ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Clinical Stage ◽  
Neuroblastoma Cell ◽  
Telomere Dysfunction ◽  
Atm Kinase ◽  
Kinase Activation ◽  
Neuroblastoma Cell Lines

AbstractCancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ∼ 25% of high-risk neuroblastomas and relapse or progression in ALT neuroblastoma patients during or after front-line therapy is frequent and almost uniformly fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell-lines and xenografts established from relapsed ALT neuroblastoma patients demonstrated de novo resistance to temozolomide + irinotecan (as SN-38 in vitro, P<0.05) and in vivo (mouse event-free survival (EFS) P<0.0001) relative to telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifest constitutive ATM kinase activation due to spontaneous telomere dysfunction while telomerase- positive tumors lacked constitutive ATM activation or spontaneous telomere DNA damage. We demonstrated that induction of telomere dysfunction resulted in ATM activation that in turn conferred resistance to temozolomide + SN-38 (4.2 fold-change in IC50, P<0.001). ATM kinase shRNA knock-down or inhibition using a clinical-stage small molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell-lines in vitro (P<0.001) and in 4 ALT xenografts in vivo (EFS P<0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. ATR inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cell lines. Thus, resistance to chemotherapy in ALT neuroblastoma occurs via ATM kinase activation and was reversed with the ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing in neuroblastoma.One Statement SummaryATM activation at telomeres confers resistance to DNA damaging chemotherapy in ALT neuroblastoma that was reversed with ATM knockdown or inhibition.

scholarly journals Ad-VT enhances the sensitivity of chemotherapy-resistant lung adenocarcinoma cells to gemcitabine and paclitaxel in vitro and in vivo

2022 ◽  
Author(s):  
Gaojie Song ◽  
Chao Shang ◽  
Lili Sun ◽  
Yiquan Li ◽  
Yilong Zhu ◽  
...  
Keyword(s):  
Cell Lines ◽  
A549 Cells ◽  
Resistance Index ◽  
Tumor Model ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Chemotherapeutic Drugs ◽  
Drug Resistant Cell

SummaryBackground One of the main challenges in the clinical treatment of lung cancer is resistance to chemotherapeutic drugs. P-glycoprotein (P-gp)-mediated drug resistance is the main obstacle to successfully implementing microtubule-targeted tumor chemotherapy. Purpose In this study, we explored the effect of Ad-hTERTp-E1a-Apoptin (Ad-VT) on drug-resistant cell lines and the molecular mechanism by which Ad-VT combined with chemotherapy affects drug-resistant cells and parental cells. Methods In vitro, cell proliferation, colony formation, resistance index (RI), apoptosis and autophagy assays were performed. Protein expression was analyzed by Western blotting. Finally, a xenograft tumor model in nude mice was used to detect tumor growth and evaluate histological characteristics. Results Our results showed that Ad-VT had an obvious killing effect on A549, A549/GEM and A549/Paclitaxel cancer cells, and the sensitivity of drug-resistant cell lines to Ad-VT was significantly higher than that of parental A549 cells. Compared with A549 cells, A549/GEM and A549/Paclitaxel cells had higher autophagy levels and higher viral replication ability. Ad-VT decreased the levels of p-PI3k, p-Akt and p-mTOR and the expression of P-gp. In vivo, Ad-VT combined with chemotherapy can effectively inhibit the growth of chemotherapy-resistant tumors and prolong the survival of mice. Conclusions Thus, the combination of Ad-VT and chemotherapeutic drugs will be a promising strategy to overcome chemoresistance.

Studies of pemetrexed and gemcitabine, alone and in combinations, in human lung cancer models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17114-17114 ◽  
Author(s):  
D. C. Chan ◽  
V. J. Chen ◽  
Z. Zhang ◽  
B. Helfrich ◽  
F. R. Hirsch ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
In Vivo Studies ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Nude Rats ◽  
Combination Regimens

17114 Background: Gemcitabine (GEM) is a deoxycytidine analog that inhibits DNA synthesis. Pemetrexed (ALIMTA, PEM) is a novel antifolate inhibiting multiple enzymes targets, including thymidylate synthase (TS). This study aimed at evaluating the antitumor effects of these antimetabolites against NSCLC and SCLC tumor models. Methods: In vitro growth inhibition (IC50) studies were done by 6-days MTT assays against a panel of 20 NSCLC and 17 SCLC cell lines. In vivo studies used only NSCLC H2122 tumor line, implanted either subcutaneously in athymic nude mice or orthotopically in athymic nude rats. Drugs were given via the ip route at the designated schedules. Results: Against NSCLC and SCLC cell lines, the averaged IC50s of GEM were 0.015 ± 0.008 μM and 0.055 ± 0.04 μM respectively. The corresponding averaged IC50s for PEM were 0.65 ± 0.2 μM and 0.091±0.018 μM respectively. When H2122 tumors reached 50–100mg, mice were treated with 10 daily doses of PEM at 100, 200 and 300 mg/kg, or three doses of GEM every 4 days at 30, 60 and 120 mg/kg. PEM delayed tumor growth by 12 to 18 days, and GEM delayed by 10 to 14 days, relative to vehicle control. Results of three combination regimens with GEM (30 mg/kg) and PEM (100 mg/kg) were: (1) GEM → PEM gave intermediate activities between the two single agents, but was toxic to animals; (2) PEM and GEM given concurrently were more active than single agents alone and delayed tumor growth by 12 days with some toxic side effects; (3) PEM → GEM was better than the single agents alone, and delayed tumor growth by ∼14 days without toxicity. Athymic nude rats bearing orthotopic H2122 tumors given PEM daily at 50, 100 and 200 mg/kg for 21 days had significantly prolonged survival, but not in a dose-dependent manner. PEM at 50 mg/kg was more effective than doses at 100 or 200 mg/kg. GEM was toxic to nude rats due to poor plasma deamination of GEM. Conclusions: In vitro, PEM was more potent against SCLC than NSCLC cell lines, but GEM had similar activities against all lung lines tested. Studies of H2122 xenografts in rodent supported PEM → GEM as the preferred sequence for the combined administration of these two drugs. [Table: see text]

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