[A mechanism of cisplatin resistance in a cisplatin resistant lung cancer cell line].
Explore the source record for details and available documents.
Cisplatin↗
Biomedical subjects
N Saijo
Publications and source records attributed to N Saijo.
[Chemosensitivity test for lung cancer].
The complete response rate in advanced non-small cell lung cancer is extremely low and the effect of chemotherapy on survival is still obscure. The emergence of resistance to anticancer agents results in the poor prognosis in small cell lung cancer although the initial response rate has improved. The significance of chemosensitivity test in lung cancer can be classified to three areas. The first of these as the individualization of chemotherapy, which means the selection of different active drugs for individual patients. In spite of numerous studies, there remain many theoretical and technical problems in predictive drug sensitivity testing. It is still far from practical use. Secondly, drug sensitivity tests have contributed to the screening of new anticancer agents. Since 1986, NCI (USA) started the disease oriented drug screening system (DOS) using human cancer cell lines. So far, active drugs against drug resistant tumors such as colon and non-small cell carcinoma have been found out by DOS. The clinical application of these drugs selected by DOS may give the answer concerning the validity of this new screening system. Thirdly, drug sensitivity tests have widely been used for the analysis of the mechanisms of drug sensitivity and resistance. By the progress of study in this field the biochemical and molecular biological targets of drug sensitivity test will be elucidated.
Antineoplastic Agents↗
In vitro evaluation of the new anticancer agents KT6149, MX-2, SM5887, menogaril, and liblomycin using cisplatin- or adriamycin-resistant human cancer cell lines.
A new model to predict antitumor activity of new analogues was developed, and the cross-resistance against cisplatin (CDDP) and Adriamycin (ADM) was examined. A preclinical evaluation of various new analogues using this new model was performed. The antitumor activities of KT6149, MX-2 (KRN8602), SM5887, menogaril (TUT-7), and liblomycin (NK313) were evaluated against four non-small cell lung cancer cell lines, PC-7, -9, -13, and -14; two small cell lung cancer cell lines, H69 and N231; four CDDP-resistant cell lines, PC-7/1.0, PC-9/0.5, PC-14/1.5, and H69/0.4; a human myelogenous leukemia cell line, K562; and its ADM-resistant subline, K562/ADM by clonogenic assay. The relative antitumor activities of these new analogues were compared with those of parental agents, mitomycin C, ADM, bleomycin, and several anticancer drugs, CDDP, daunomycin, vindesine, and etoposide. KT6149 was more active than mitomycin C against all lung cancer cell lines and the human myelogenous leukemia cell line. Menogaril showed greater activity than ADM, and MX-2 showed activity similar to ADM. However, the antitumor activity of SM5887 was lower than that of ADM. SM5887 and menogaril showed cross-resistance to K562/ADM. Nevertheless, the antitumor activity against K562/ADM of MX-2 was similar to that of the parental cell lines. The activity of liblomycin was similar to that of bleomycin. Thus, KT6149 appears to be the best analogue for use in a clinical trial against lung cancer. MX-2 was active even against ADM-resistant cancer cells. The values of relative resistance to CDDP or ADM were 4.7, 8.1, 7.5, 20.0, and 13.6 for PC-7/1.0, PC-9/0.5, PC-14/1.5, H69/0.4, and K562/ADM, respectively. CDDP-resistant cell lines showed no cross-resistance with other drugs in this study. K562/ADM showed cross-resistance against daunomycin, etoposide, and vindesine. In contrast, mitomycin C and bleomycin had nearly equal activity against K562 and K562/ADM. However, K562/ADM was 2.4-fold more sensitive to CDDP than its parental cell line, K562 (P less than 0.001). These results suggested that the mechanism of CDDP resistance is different from that of multidrug resistance.
Anthracyclines↗
Immunoreactive gastrin-releasing peptide as a specific tumor marker in patients with small cell lung carcinoma.
Gastrin-releasing peptide (GRP) is now known to be a very common product of small cell lung carcinoma (SCLC). With the aim of investigating the possible role of this peptide as a tumor marker of SCLC, we have developed a sensitive radioimmunoassay system for plasma immunoreactive GRP using immune-affinity chromatography for plasma extraction. Plasma immunoreactive GRP levels in control subjects were determined by using 15 ml of plasma as the starting material (minimum concentration detectable, 0.8 pg/ml). The levels in 10 control subjects were (mean +/- SD) 1.2 +/- 0.27 pg/ml; range, 0.86-1.7 pg/ml. This assay system was applied for the clinical use by using 3 ml of plasma as the starting material (minimum concentration detectable, 4.0 pg/ml). Plasma immunoreactive GRP levels were elevated in SCLC patients at frequencies of 71% in patients with limited disease and 80% in those with extensive disease. Furthermore, a change in the level showed excellent correlation with the therapeutic response. In six patients with complete response who had had elevated levels before treatment, the levels decreased to an undetectable range when the tumor disappeared, and they remained undetectable until 1 month later, when the patients were judged to have achieved complete response. In the partial response group, plasma immunoreactive GRP levels had decreased to an undetectable level in two of three patients, when the patients achieved partial response. In four patients with progressive disease, plasma immunoreactive GRP levels were elevated at the time of the progressive disease judgment, when compared with levels before treatment. The levels in 21 patients with non-SCLC (10 with adenocarcinoma, seven with squamous cell carcinoma and four with large cell carcinoma) were not elevated. These results indicate the plasma immunoreactive GRP level as a useful tumor marker in SCLC patients. It is now believed that GRP can function as an autocrine growth factor for SCLC. The present study suggests that the possible autocrine growth factor could serve as a reliable tumor marker for cancer patients.
Adenocarcinoma↗
Phase I study of combination therapy with interleukin 2 and beta-interferon in patients with advanced malignancy.
Based on a preclinical study demonstrating the synergistic antitumor effect of recombinant interleukin 2 (rIL-2) and beta-interferon (IFN-beta) on mouse tumors and previous results of a phase I study of rIL-2, a phase I study of combination therapy with human rIL-2 and IFN-beta was conducted in 26 patients with advanced malignancy. Patients were given rIL-2 by 24-h continuous i.v. infusion and IFN-beta by 2-h i.v. infusion for 5 days each week for 4 weeks. The common side-effects were fever, malaise, chills, appetite loss, and diarrhea. Leukocytosis and eosinophilia were observed in 56% and 69% of the patients, respectively. Transient leukopenia and thrombocytopenia were also observed in some patients. Dose-limiting manifestations were intolerable fatigue and liver dysfunction, and it was concluded that the maximum tolerated doses of rIL-2 combined with IFN-beta were 1.1 x 10(6) U/m2/day for rIL-2 and 6.0 x 10(6) IU/m2/day for IFN-beta. No patients achieved complete and partial response to therapy in this study. One patient with pulmonary metastasis from pharyngeal cancer showed a minor response. Natural killer (NK) and lymphokine-activated killer (LAK) activities increased during the 5 days of treatment and decreased during the 2-day intermission. The percentage of IL-2 receptor-positive cells increased markedly until Day 12, and gradually decreased thereafter. The percentage of OKT 4-positive cells and the OKT 4/OKT 8 ratio increased. In contrast, the percentage of Leu 7- or Leu 11-positive cells decreased over the 4-week treatment. A phase II study of this combination therapy is ongoing against head and neck cancer, and renal cell carcinoma.
Adult↗
Serial measurement of sister chromatid exchanges in the peripheral lymphocytes of patients with lung cancer receiving chemotherapy in relation to bone marrow toxicity.
The frequencies of sister chromatid exchanges (SCE) in the peripheral lymphocytes of patients with lung cancer before and after initial chemotherapy were serially measured and the correlation between SCE frequencies and bone marrow toxicity was evaluated. The addition of mitomycin C to vindesine plus cisplatin increased SCE frequencies significantly in patients with non-small cell lung cancer. A significant increase in frequencies of SCE was observed in patients treated with cyclophosphamide plus adriamycin plus vincristine as compared with those treated with cisplatin plus etoposide in small cell lung cancer. A significant inverse correlation was observed between SCE frequencies in the peripheral lymphocytes 7 days after treatment (x) and the nadir value/pretreatment value of platelets (y)(r = -0.685, P = 0.0007, y = 0.842-0.022x). The relation between SCE frequency and leukopenia showed the same trend as thrombocytopenia, but the correlation was not statistically significant (r = -0.444, P = 0.057). SCE assay may have potential clinical use for the prediction of chemotherapy-induced thrombocytopenia.
Antineoplastic Combined Chemotherapy Protocols↗
Inhibition of colony formation of drug-resistant human tumor cell lines by combinations of interleukin-2-activated killer cells and antitumor drugs.
The cytotoxicity of interleukin-2-activated killer (LAK) cells with or without anticancer drugs against cell lines with acquired drug resistance was evaluated in vitro by colony assay. Human non-small cell lung cancer cell lines, PC-9 and PC-14, human leukemia cell line, K-562, and their sublines resistant to cisplatin (CDDP), PC-9/CDDP and PC-14/CDDP, and to adriamycin (ADM), K-562/ADM, were used as target cells. PC-9/CDDP demonstrated a marked increase in susceptibility to killing by both peripheral blood lymphocytes (PBL) and LAK cells, as compared to the parental cell line, PC-9. The cytotoxicity of PBL and LAK cells against PC-14/CDDP and K-562/ADM was similar to that against their parental cell lines. Moreover, the combination of LAK and CDDP had a synergistic effect on PC-14 and PC-14/CDDP.
Adenocarcinoma↗
[Clinical application of human recombinant colony stimulating factor].
Explore the source record for details and available documents.
Animals↗
Phase II study of carboplatin in non-small cell lung cancer.
Forty four patients with advanced non-small cell lung cancer (NSCLC) were treated with carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) at a dose of 400-450 mg/m2 intravenously every four weeks in a phase II study. Forty three patients were evaluated for response and toxicity. Two patients achieved responses resulting in an overall response rate of 4.7% (95% confidence limits: 0.6-15.8%); one of these had not been treated previously and the other had been treated previously with vinblastine. The durations of their responses were 5 and 7 months, respectively. The response rate in 28 previously untreated patients was 3.6% (1/28; 95% confidence limits: 0.1-18.3%). Myelosuppression was the most commonly found toxicity, and thrombocytopenia especially was dose-limiting. Thrombocytopenia (less than 75,000/mm3) was observed in 12 patients (28%). Leukopenia (less than 3,000/mm3) was observed in 14 patients (33%). No serious infection or bleeding occurred, however. Treatment with 400-450 mg CBDCA/m2 was well tolerated in the good risk patients in this study. Mild to moderate emesis was observed in 28 patients (65%). No renal toxicity, neurotoxicity or ototoxicity was seen. It was demonstrated that CBDCA had little efficacy in NSCLC at the dose and schedule given in the present study.
Adult↗
[Effects of recombinant human colony stimulating factor (rh-CSFs) on colony formation of lung cancer cell lines].
Explore the source record for details and available documents.
Adenocarcinoma↗
[The meaning and prospect of chemosensitivity tests].
Explore the source record for details and available documents.
Animals↗
Control of cisplatin-induced delayed emesis with metoclopramide and dexamethasone: a randomized controlled trial.
Forty-two patients with advanced lung cancer undergoing chemotherapy containing cisplatin (80 mg/m2) were submitted to a randomized controlled trial to evaluate the effect of the combination of metoclopramide and dexamethasone for the treatment of delayed cisplatin-induced emesis occurring more than 24 hours after cisplatin administration. All patients received intravenously (i.v.) high-dose metoclopramide and dexamethasone on the day of cisplatin treatment. Excellent emetic control (no emesis during the 24 hours following cisplatin administration) was achieved in 30 out of 41 patients (73%) with this combination. Patients treated i.v. with metoclopramide and dexamethasone on days 2-7 experienced less delayed emesis, nausea and anorexia compared to those treated with a placebo (delayed emesis, 25 vs 50%, respectively, P = 0.105; more than four days of nausea, 10 vs 35%, respectively, P = 0.059; less than three days of anorexia, 80 vs 50%, respectively, P = 0.048). Although the results of the study showed no statistically significant advantage with the combination of i.v. metoclopramide and dexamethasone for patients treated with cisplatin, in view of the short duration of anorexia and the marginal reduction in nausea. Female patients tended to have more emetic episodes and extrapyramidal side effects (except akathisia) than male patients, but the differences were not statistically significant except for acute emesis (P less than 0.005).
Adult↗
Evaluation of the effects of chemotherapy in lung cancer by thoracic computed tomography.
In thoracic-computed tomography (CT) before and after chemotherapy against lung cancer in 23 patients, the percentages of the reduction of tumor size were calculated by three different methods of measurements, including (1) the product of the largest perpendicular diameter of the tumor, (2) the area of the tumor determined by the tracing method on the image which has the largest tumor mass visualized, and (3) the sum of the areas of all tumors measured by the tracing method. The tumor reduction percentages measured by these three different methods showed good correlation (1 versus 2, 2 versus 3, 3 versus 1; P less than 0.001). Therefore, it was assumed that the percentage of tumor reduction determined by the thoracic CT can be calculated correctly by the product of the perpendicular diameters of tumors on the selection of the image which has the largest tumor mass visualized.
Adult↗
Establishment and characterization of cisplatin-resistant sublines of human lung cancer cell lines.
Human lung cancer sublines resistant to cisplatin (CDDP) have been developed by continuously exposing cells to gradually increasing doses of CDDP and use of the limiting dilution technique. The cell lines used were PC-7, PC-9 and PC-14 (pulmonary adenocarcinoma) and H69 and N231 (small-cell lung cancer). The resistant phenotype of the resistant sublines was stable for more than 2 months in the absence of drug. PC-7/1.2 (i.e., PC-7 cells growing stably in medium containing 1.2 micrograms/ml of CDDP), PC-9/0.5, PC-14/1.5, H69/0.4, and N231/0.2 have been developed, which are 22.9, 7.1, 3.1, 25.6, and 8.4 times more resistant to CDDP than the respective parent cell line in terms of IC50 in the soft agar colony assay with continuous drug exposure. Cloning efficiency decreased significantly in N231/0.2. The doubling times increased significantly in most of the resistant sublines. Cellular DNA contents increased in all resistant sublines, but statistical significance was observed only in H69/0.4 (p less than 0.05). Cells of the resistant sublines of PC-7, PC-9, PC-14 and H69 were larger than cells of the parent lines, but the differences were not significant. The growth morphologies of all resistant sublines in the drug-free medium were similar to those of parent cell lines. All resistant sublines tested were significantly cross-resistant to carboplatin. The patterns of cross-resistance, cross-sensitivity and collateral sensitivity to adriamycin, mitomycin-C, 5-fluorouracil, vindesine, etoposide, aclacinomycin and vincristine were different in each resistant subline. Verapamil (3.3 micrograms/ml) showed little modifying effect on CDDP resistance in 5 CDDP-resistant sublines tested except N231/0.2 (Modification Index: 0.49). Cyclosporin A (5.0 micrograms/ml) modified CDDP resistance in CDDP-resistant small-cell lung cancer sublines (H69/0.4 and N231/0.2) (Modification Index: 0.45 and 0.07, respectively), while in CDDP-resistant NSCLC sublines (PC-7/1.0 and PC-9/0.5), cyclosporin A reduced the sensitivity to CDDP.
Cell Line↗
In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors.
We have used several transplantable experimental murine tumors to evaluate the potentiation of antitumor activity by a combination of human recombinant interleukin 2 (rHIL2) and recombinant interferons (rIFNs). The combination of rHIL2 and either human hybrid recombinant alpha-interferon A/D (rIFN-alpha A/D) or mouse recombinant beta-interferon (rIFN-beta) induced the s.c. adenocarcinoma 755, which had been established for 8 days, to regress, although rHIL2 or the rIFNs alone hardly inhibited the tumor's growth. Eight injections of the rHIL2-rIFN-alpha A/D combination cured 38% of the tumor-bearing mice. The rHIL2-rIFN-beta combination achieved a complete cure only when given in more than 13 injections. The administration of rHIL2 and mouse recombinant gamma-interferon (rIFN-gamma) markedly inhibited tumor growth of the s.c. established adenocarcinoma 755, but did not cure any of the mice. Other tumors, B16-F10 melanoma, and colon tumors 38 and 26 responded almost as well to a rHIL2-rIFN-alpha A/D or -beta combination, but not to a rHIL2-rIFN-gamma combination. The growth of Lewis lung carcinoma was inhibited to a lesser extent by all combinations, for which there were no long-term survivors. The combination therapy of rHIL2 and rIFN-beta produced a marked regression of the tumor in beige mice which have low natural killer activity, suggesting the activated natural killer cells not to be responsible for the therapeutic effect. And T-cell immunity may be important in the regression of s.c. established tumors, because of the lesser potentiation of antitumor activity in athymic mice. These results demonstrate that combination therapies of rHIL2 and rIFN-alpha A/D or -beta can function synergistically in the various s.c. established murine tumor systems and give further evidence in support of their clinical potential.
Animals↗
Comparative study of the antitumor effect of two types of murine recombinant interferons, (beta) and (gamma), against B16-F10 melanoma.
A comparative study of the antitumor effect of murine recombinant interferon(beta) less than Mu-rIFN(beta) greater than and murine recombinant interferon(gamma) less than Mu-rIFN(gamma) greater on B16-F10 melanoma was conducted. Administration of Mu-rIFN(gamma) i.p. into C57BL/6 mice on days 1 to 7 produced a higher suppressive effect than Mu-rIFN(beta) both on the growth of s.c. implanted tumor and on the formation of artificial pulmonary metastasis. Pharmacokinetic study of Mu-rIFN(gamma) demonstrated that high plasma levels were retained for a long time. In clonogenic assay, Mu-rIFN(gamma) at 1000 units/ml showed about 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN(beta) hardly inhibited the colonies, even at 1000 units/ml. Augmentation of natural killer (NK) cytotoxicity was much greater with Mu-rIFN(beta) than Mu-rIFN(gamma), whereas Mu-rIFN(gamma) enhanced the cytotoxicity of peritoneal macrophages more strongly than Mu-rIFN(beta). Injection of Mu-rIFN(gamma) i.p. 1 day before tumor challenge also inhibited the formation of pulmonary metastasis of B16-F10 melanoma. However, pretreatment of mice with carrageenan significantly suppressed the inhibitory effect of Mu-rIFN(gamma). From these results, it is suggested that the inhibitory effect of Mu-rIFN(gamma) on the tumor growth and metastases of B16-F10 melanoma is mediated partly by direct antitumor effect and partly by the activation of macrophages, and that the augmentation of NK activity contributes mainly to the antitumor effect of Mu-rIFN(beta).
Animals↗
Cytogenetic effect of carboplatin on human lymphocytes.
Carboplatin, a second generation cisplatin analogue, was tested for induction of sister chromatid exchange (SCE) as well as chromosomal aberrations in human lymphocytes in vitro and in vivo. A dose-dependent effect was observed for increased frequency of metaphases with SCE (r = 0.984, P less than 0.001) as well as chromosomal aberrations (r = 0.994, P less than 0.001), primarily chromatid gap or break, in vitro. SCE induction by carboplatin was less than that by cisplatin at the same concentration. When patients were treated with a single dose of carboplatin at a dose of 450 mg/m2, the frequency of SCE and chromatid type aberrations increased significantly. However, even when considering dose and peak plasma concentration in patients receiving carboplatin, it appears that the ability of carboplatin to induce SCE and chromosomal aberrations is weaker than that of cisplatin. SCE frequencies induced by carboplatin decreased with time going by, and in one patient who was tested 5 weeks after treatment, SCE frequency showed a decrease to the pretreatment level. It thus appears that carboplatin has an improved therapeutic index over the parent compound, cisplatin, because of its less mutagenic or carcinogenic hazard, in addition to the largely reduced incidence of untoward effects.
Aged↗
In vitro antitumor activity of mitomycin C derivative (RM-49) and new anticancer antibiotics (FK973) against lung cancer cell lines determined by tetrazolium dye (MTT) assay.
Seven small- (SCLC) and four non-small-cell (NSCLC) lung cancer cell lines were used to examine the in vitro cytotoxicity of cytotoxic drugs such as (1aS-(1a alpha,8 beta,8a alpha,8b alpha]-8-[aminocarbonyl)oxy)methyl)-4,8a- dimethoxy-1,1a,2,8,8a,8b-hexahydro-7-hydroxy-5-methyl-6- nitrosoazirino(2',3':3,4)-pyrrolo-(1,2-a)indole (RM-49) and 11-acetyl-8-carboxymethyl-4-formyl-14oxa-1,11-diaze- tetracyclo(7.4.1.0(2,7),0(10,12]tetradeca-2-4-6-trien-6,9-++ +diyl-diacetate (FK973). In vitro cytotoxicities of RM-49 and FK973 were compared with those of mitomycin C (MMC), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP16), adriamycin (ADM) and vindesin (VDS). Drug sensitivity was determined using a tetrazolium (MTT)-based assay. Average IC50 values of these two drugs were not statistically different compared with that of MMC, although FK973 showed strong antitumor activity against SCLC cell lines such as LT3, N857, and H69 at the same concentration. The predicted peak plasma concentration (predicted PPC) calculated by the formula proposed by Scheithauer, log (predicted PPC) = -0.788 + (0.755 x log(LD50], and relative antitumor activity, RAA (PPC/IC50), of RM-49 were higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05), and those of FK973 were also higher than those of other drugs such as MMC, CDDP, CBDCA, and ADM against SCLC cell lines (P less than or equal to 0.05). Based on these promising in vitro studies, the clinical trials of RM-49 and FK973 were warranted.
Antibiotics, Antineoplastic↗