thioinosine and Lung-Neoplasms

Gemcitabine is one of the most commonly used agents for lung cancer chemotherapy, but the determinants of sensitivity and/or resistance to this agent are not yet fully understood. In this study we used quantitative RT-PCR to examine the expression levels of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) genes in non-small cell lung cancer (NSCLC) cell lines in relation to sensitivity and resistance to gemcitabine. The basal expression levels of hENT1 were significantly correlated with the IC50 values for gemcitabine (r =-0.6769, P = 0.0005), whereas dCK expression levels were not. In a highly gemcitabine-sensitive cell line, NCI-H23, the sensitivity to gemcitabine was inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of hENT1, without significant modulation of hENT1 expression. These data suggest that hENT1 is associated with gemcitabine sensitivity in lung cancer. We also continuously exposed NCI-H23 cells to gemcitabine and subsequently established the drug-resistant clone H23/GEM-R, which showed a significant decrease of dCK expression; however, hENT1 expression was not altered in the continuously exposed sublines or in the resistant clone. We conclude that increased hENT1 expression is a determinant of gemcitabine sensitivity, while decreased dCK expression is associated with acquired resistance to gemcitabine in NSCLC cells. Thus, hENT1 and dCK might be useful as predictive markers for efficacy of gemcitabine therapy in NSCLC.

Topics: Affinity Labels; Antimetabolites, Antineoplastic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Division; Deoxycytidine; Deoxycytidine Kinase; Drug Resistance, Neoplasm; Equilibrative Nucleoside Transporter 1; Gemcitabine; Humans; Lung Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Thioinosine; Tumor Cells, Cultured

To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cornea; Cyclophosphamide; Drug Administration Schedule; Drug Carriers; Drug Resistance, Multiple; Female; Fluorouracil; Genes, p53; Leukemia L1210; Liposomes; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Neovascularization, Pathologic; Neovascularization, Physiologic; Thioinosine

Nitrobenzylthioinosine (NBMPR), a potent inhibitor of facilitated nucleoside transport in vitro and in vivo, and acyclothymidine (ACT), a potent inhibitor of pyrimidine nucleoside phosphorylase in vitro, have been used in an attempt to modulate the biodistribution of 125I-labelled iododeoxyuridine ([125I]IUdR). ACT or NBMPR-P (a water-soluble prodrug of NBMPR) were injected into BDF1 mice bearing implanted Lewis lung tumors, according to protocols which would provide high and low plasma levels of the inhibitor. Compared with controls, both inhibitors induced transient, marginal increases in hepatic, renal and blood levels of [125I]IUdR, and decreased levels in tumors at short time intervals after injection. It is concluded that there is a mild tumor-sparing effect when either NBMPR or ACT are administered together with single i.v. diagnostic doses of [125I]IUdR.

Topics: Animals; Idoxuridine; Inosine; Iodine Radioisotopes; Lung Neoplasms; Male; Mice; Neoplasm Transplantation; Radionuclide Imaging; Stimulation, Chemical; Thioinosine; Thionucleotides; Tissue Distribution; Uracil

Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), a water-soluble form of the nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) was administered by i.v. injection to normal mice and BDF1 mice with implanted Lewis Lung carcinomas. Tritiated 5-Fluoro-2'-deoxyuridine (3H-FUdR) was injected either alone (control), 10 min before (I + 10), 10 min (I - 10) after, 60 min (I - 60) after, or simultaneously (I = 0) with the transport inhibitor. Tissue distributions of tritium were determined after intervals of 1, 2 and 4 h. The per cent of injected radioactivity (% dose) in liver was increased by all NBMPR-P protocols. Kidney radioactivity was similarly affected, with maximum increases (from 9.3 +/- 3.4 to 24.1 +/- 5.2% of the injected dose/g) after 1 h in the I - 60 animals. No statistically significant changes in the distribution of radioactivity in tumor, spleen, marrow or blood were induced by doses of NBMPR-P. Elevated levels of tritium radioactivity in blood were accompanied by similar increases in renal and hepatic radioactivity. The apparent increase in the tumor uptake of 3H-FUdR (from 1.4 +/- 0.2 to 5.7 +/- 2.3% dose/g) was not statistically significant at the 95% confidence limit. In general, NBMPR-P induced a relative tumor-sparing effect and at the same time increased uptake of 3H-FUdR by the liver and kidney, or delayed its clearance from these organs. There was no evidence to suggest that any advantage would be gained by using NBMPR-P treatment in conjunction with radiolabelled FUdR for tumor diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Floxuridine; Inosine; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Radionuclide Imaging; Thioinosine; Thionucleotides; Tissue Distribution; Tritium