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Biomedical subjects

W S Hong

Publications and source records attributed to W S Hong.

At least 37 records · Page 2Linked to original sources
PubMed1995

Over-expression of p53 protein in squamous cell carcinoma of the skin.

p53 gene mutations have been known to be highly related to the particular stage of transformation in various types of human cancers. This study was conducted to investigate the p53 mutations at the protein level by an immunohistochemical method using anti-p53 antibody, NCL-p53-DO-7. Twenty-five cancer specimens were obtained surgically from patients with squamous cell cancer of the skin at the Korea Cancer Center Hospital. The cancers were classified according to the possible etiology into two groups, burn scar originated and UV-related cancers. Overexpression of p53 protein was detected in ten (40%) out of 25 cases tested: six (40%) of 15 cases associated with burn scar and four (40%) of ten cases related to UV exposure. In all normal skin cells in specimens, p53 protein was not stained at all. The stages and histological grades were evaluated for their relationship with the overexpression of p53 protein. No significant difference was found between the overexpression of p53 protein and the stages or histological grades. These results demonstrating that 40% of skin cancers were positive for p53 overexpression suggest that the alterations of the p53 gene may play a role and the exact role of p53 gene in the development of squamous cell carcinoma of the skin will be studied.

Adult↗
PubMed1995

Peripheral blood lymphocyte subsets in patients with stomach cancer.

The present study was conducted in order to investigate the immunologic alterations alongside the numerical changes in peripheral blood lymphocytes(PBL) and their subsets in stomach cancer patients. Lymphocyte surface markers were determined in 85 stomach cancer patients and 49 controls by indirect immunofluorescence technique using monoclonal antibodies. Monoclonal antibodies used were Leu 2a(CD8, suppressor/cytotoxic T cells), Leu 3a(CD4, inducer/helper T cells), Leu 4(CD3, pan T reagent), Leu 11(CD16, natural killer cells) and Leu 12(CD19, B cells). The numbers of PBL, CD3+, CD4+, CD8+, CD16+ and CD19+ cells significantly decreased and the CD4: CD8 value increased in 85 patients with stomach cancer compared to those in controls(p < 0.01). In stage I(n = 17), neither PBL, their subsets nor the CD4: CD8 value were significantly different from those of the controls. In stage II(n = 17), the numbers of PBL, CD3+, CD4+ and CD8+ cells decreased(p < 0.01). In stage III(n = 24) and IV(n = 27), PBL and all subsets measured decreased(p < 0.01). The CD4: CD8 value showed significant increases in stages III and IV(p < 0.01), because the CD8+ cells decreased to a greater extent than did the CD4+ cells. The results demonstrating that the lymphocyte subsets are depressed differentially with the stage suggest that host immunity is impaired with the progression of stomach cancer.

Adult↗
PubMed1995

Antitumor activity of five new platinum complexes having a glycolate leaving ligand.

In an attempt to develop a new anticancer platinum complex with greater or equivalent antitumor activity but reduced side effects compared with cisplatin (CDDP), a series of new platinum complexes having a glycolate leaving ligand was synthesized. Among them, five complexes were selected for further development on the basis of adequate water solubility, low nephrotoxicity and high antitumor activity in a murine system. The chemosensitivity of these five complexes was examined in MTT assay against two human pulmonary adenocarcinoma cell lines, PC-9 and PC-14, and two human stomach adenocarcinoma cell lines, MKN-45 and KATO III. Their IC50 and relative antitumor activity (RAA) values were compared with those of CDDP and 254-S, a second-generation platinum complex with a glycolate leaving ligand under phase III clinical trial. The lowest mean IC50 value was observed in CDDP, followed by SKI 2034R and SKI 2033R. In this study, the antitumor activity was evaluated in terms of RAA values and SKI 2034R showed the highest RAA value. The order of RAA values was SKI 2034R > CDDP > SKI 2032R > SKI 2033R > SKI 2030R > SKI 2029R > 254-S. Based on the RAA order, we have recommended SKI 2034R as the most promising candidate for further development of a clinically useful platinum complex.

Antineoplastic Agents↗
PubMed1995

Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II), as determined by ex vivo pharmacodynamics.

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

Animals↗
PubMed1994

Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes.

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.

Animals↗
PubMed1994

Aberrant expression of p53 gene product in malignant melanoma.

According to the current concept of carcinogenesis, the alterations of p53 tumor suppressor gene have been the most frequently detected in both human cancer cell lines and cancer tissues freshly isolated. This study was conducted to investigate the p53 gene alteration in malignant melanoma. Nineteen tumor tissues were obtained from 19 patients with malignant melanoma and examined for the expression of p53 protein by immunohistochemical staining with mouse monoclonal anti-p53 antibody, NCL-p53-DO-7. Twelve out of 19 cases (63%) showed positive reactions for p53 protein: 26, 21 and 16% of which had low, intermediate and high reactivity, respectively. p53 alteration more frequently expressed in female (10/12) than male patients (2/7) with malignant melanoma (p < 0.05). The incidence of expression of p53 protein was compared according to the stages and the sites of tissue obtained. The positive rate for p53 protein was not significantly different between the stages. The positive rates for p53 protein were five out of five (100%), one out of two (50%) and six out of twelve (50%) in tissues obtained from the metastatic, lymph node, and primary sites, respectively. The difference in the positive rates, however, is not statistically significant. These results suggest that p53 gene is a frequent target for mutation in the development of malignant melanoma.

Adult↗
PubMed1994

Effect of non-tumor cell contamination on detection of p53 gene mutations in human gastric cancer cells by polymerase chain reaction single-strand conformation polymorphism analysis.

BACKGROUND: We have previously studied p53 gene mutations in 25 primary gastric cancer tissues by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis for exon 4-8 and immunohistochemical staining with anti-p53 antibody. In four cases, the discrepancy of the results was observed between the two methods. In one case positive by PCR-SSCP but negative by immunohistochemical staining, the mutation was silent. In three cases, the p53 gene mutations were detected only by immunohistochemical staining. This discrepancy may be due to the contamination of the samples by cells without p53 gene mutation, such as non-tumor cells. This study was conducted to investigate the sensitivity of PCR-SSCP analysis to p53 gene mutations when the sample was contaminated with non-tumor cells. METHODS: Genomic DNA was extracted by the digestion with proteinase K and phenol-chloroform-ethanol method from two human gastric adenocarcinoma cell lines, MKN-45 and KATO III. To investigate the sensitivity of PCR-SSCP, DNA extracted from cancer cells was mixed with DNA obtained from normal gastric mucosal cells at various ratios. PCR-SSCP analysis for exon 4-8 of the p53 gene was performed with the mixed DNA samples. RESULTS: In KATO III, no PCR products were generated in exon 4-8 of the p53 gene by PCR, suggesting that both alleles from exon 4-8 of the p53 gene were deleted. In MKN-45, the mobility shift was observed in exon 4. Therefore, the effect of non-tumor cell contamination on the detection of p53 gene mutations was conducted using MKN-45 and normal gastric mucosal cells. In the mixed DNA samples of MKN-45 and normal gastric mucosal cells, an extra band with the migration similar to that of MKN-45 was found in the samples of 1:8 dilution or less, while no extra band was grossly detectable in DNA of normal gastric mucosal cells and in the samples of more than 1:16 dilution. CONCLUSIONS: These results suggest that the detection of p53 mutations by PCR-SSCP analysis may be underestimated in samples contaminated by a large number of non-tumor cells.

Base Sequence↗
PubMed1993

Loss of retinoblastoma gene and amplification of N-myc gene in retinoblastoma.

We have analyzed paired samples of genomic DNA from peripheral leukocyte and primary tumor tissue from nine patients with retinoblastoma (RB) and from two RB cell lines, WERI-Rb-1 and Y79, to detect the molecular alterations of the retinoblastoma susceptibility gene (RB-1) and N-myc gene. In Southern analysis, RB-1 deletions in tumor tissues were detected in five patients (56%), one of these revealed a total loss of RB-1. N-myc amplification was found only in one (11.1%) out of nine patients. We also observed a total loss of RB-1 in WERI-Rb-1, and a more than 100-fold amplification of N-myc in Y79. The analysis of the relationship between molecular events and clinical characteristics such as age, sex, tumor laterality did not reveal any specific correlation. These results suggest that genetic backgrounds of RB in Korean patients are quite similar to those of reported cases elsewhere. The high sensitivity of our method in detecting the RB-1 loss indicates that this method can be a useful tool for initially screening a large number of tumors.

Child↗
PubMed1993

Chemosensitization to adriamycin by cyclosporin A and verapamil in human retinoblastoma cell lines.

The chemosensitizing effects of cyclosporin A and verapamil on the cytotoxicity of adriamycin were investigated using MTT assay against two human retinoblastoma cell lines, Y79 and WERI-Rb-1. Y79 and WERI-Rb-1 were totally resistant to doses up to 5.0 micrograms/ml of verapamil. Cyclosporin A inhibited the survival of Y79 and WERI-Rb-1 dose-dependently, however, the maximum inhibition at the highest concentration tested (5.0 micrograms/ml) was less than 50% (% survival at 5.0 micrograms/ml of cyclosporin A: 65.6% and 66.9% in Y79 and WERI-Rb-1, respectively). Combination of cyclosporin A and verapamil did not further inhibit the survival of Y79 and WERI-Rb-1 compared with cyclosporin A alone. Adramycin inhibited the survival of Y79 and WERI-Rb-1 dose-dependently. The chemosensitizing effects of cyclosporin A and verapamil on the cytotoxicity of adriamycin were evaluated in terms of sensitizing index (SI: the ratio of IC50 to adriamycin alone to IC50 to adriamycin in the presence of cyclosporin A and/or verapamil). Cyclosporin A significantly enhanced SI and the addition of verapamil enhanced SI further: SI values at 5.0 micrograms/ml of cyclosporin A, 5.0 micrograms/ml of cyclosporin A plus 1.5 micrograms/ml of cyclosporin A plus 1.5 micrograms/ml of verapamil, 5.0 micrograms/ml of cyclosporin A plus 3.0 micrograms/ml of verapamil were 2.0, 2.6 and 2.8 in Y79 and 2.6, 5.8 and 9.7 in WERI-Rb-1, respectively. These results suggest that cyclosporin A and verapamil are promising chemosensitizers to adriamycin in the treatment of retinoblastoma.

Cell Survival↗
PubMed1992

Modification of adriamycin-induced cytotoxicity by recombinant human interferon-gamma and/or verapamil in human stomach cancer cells.

Recombinant human-interferon-gamma (rH-IFN-gamma) and verapamil (VRP), either alone or in combination, were evaluated in MTT assay for their modification effects on adriamycin-induced cytotoxicity against MKN-45, human stomach adenocarcinoma cells. VRP as a single agent did not inhibit the survival of MKN-45 at doses of up to 5.0 micrograms/ml. The survival of MKN-45 was inhibited by rH-IFN-gamma dose-dependently and further inhibited by the addition of VRP. However, the maximum growth inhibition of MKN-45 in any combination treatment with rH-IFN-gamma and VRP was less than 50% except in the highest concentration combinations (% survival: 47.9% at 10(4) U/ml of rH-IFN-gamma and 3.0 micrograms/ml of VRP). Adriamycin caused a concentration-dependent cytotoxicity and its cytotoxicity was significantly enhanced by the addition of rH-IFN-gamma and further enhanced by the combined use of rH-IFN-gamma and VRP. The modification effects of rH-IFN-gamma and VRP on adriamycin-induced cytotoxicity were evaluated in terms of modification index (MI), demonstrating that rH-IFN-gamma significantly increased in adriamycin-induced cytotoxicity and that the combined use of rH-IFN-gamma and VRP enhanced the adriamycin-induced cytotoxicity to a greater extent than did rH-IFN-gamma alone: MI values at 10(2) U/ml and 10(3) U/ml of rH-IFN-gamma were 1.7 and 3.1, respectively; those at 1.5 micrograms/ml and 3.0 micrograms/ml of VRP in the presence of 10(3) U/ml of rH-IFN-gamma were 4.4 and 6.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1991

Differential depression of lymphocyte subsets according to stage in stomach cancer.

Lymphocyte surface markers were determined in the peripheral blood lymphocytes (PBL) in 31 stomach cancer patients (15 males and 16 females) and 47 controls (20 males and 27 females) using an indirect immunofluorescence technique. The monoclonal antibodies used were Leu 2a (CD8, suppressor/cytotoxic T cells), Leu 3a (CD4, inducer/helper T cells), Leu 4 (CD3, pan T reagent), Leu 11 (CD16, natural killer cells) and Leu 12 (CD19, B cells). The numbers of PBL, CD3+, CD4+, CD8+, CD16+ and CD19+ cells significantly decreased and the CD4:CD8 value increased in patients with stomach cancer compared to those in healthy volunteers. In stage I, PBL, none of the PBL subsets nor the CD4:CD8 value were significantly different from those of the controls. In stage II, the numbers of PBL, CD3+, CD4+ and CD8+ cells decreased. In stage III, the CD19+ cells decreased in addition to the decreased subsets in stage II. In stage IV, PBL and all subsets measured decreased. The CD4:CD8 value showed significant increases in stages II, III and IV, because the CD8+ cells decreased to a greater extent than did the CD4+ cells. Changes in the subsets were analyzed with regard to age, sex, performance status and smoking history, no significant relation being observed between these factors and lymphocyte subsets. From the present study, we have demonstrated that lymphocyte subsets were differentially depressed in the order of T cells, B cells and natural killer cells, with progression of the stage of disease.

Adult↗
PubMed1991

Clinical usefulness of alpha-1-antitrypsin in the diagnosis of hepatocellular carcinoma.

Serum levels of alpha-1-Antitrypsin(AAT) were determined in 42 patients with hepatocellular carcinoma(HCC), 5 patients with metastatic liver cancer from stomach adenocarcinoma, 10 patients with liver cirrhosis, 10 patients with chronic hepatitis, and 66 controls by rocket immunoelectrophoresis using rabbit antiserum. The mean level of serum AAT was 225.5 +/- 73.0 mg/dl in 66 controls. The serum AAT in patients with HCC was 428.7 +/- 123.3 mg/dl, which was significantly higher than those in the controls and in patients with liver cirrhosis or chronic hepatitis(p less than 0.02). The level of AAT in metastatic liver cancer was similar to that in HCC. The positive cut-off value for elevation of serum AAT in this study was determined as above 445 mg/dl, the mean plus 3 standard deviations in the controls. Elevations of serum AAT were observed in 54.8%, 60.0%, and 10.0% of patients with HCC, metastatic liver cancer, and liver cirrhosis, respectively, while none of the patients with chronic hepatitis or the controls was positive. The serum AAT levels in 42 patients with HCC were analyzed with regard to sex, age, serum albumin, HBsAg, alpha-fetoprotein(AFP), and diameter of HCC, with no significant differences being observed between these factors and the serum AAT levels except for the diameter of the HCC. The positive rate in the HCC with a diameter of 10 cm or more was 74.1%, which was a significantly higher rate compared with 20.0% in the HCC with diameters less than 10cm. The positive rate of AFP for HCC was 61.9%, when 500 ng/ml of AFP was used as the cut-off value.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Defective response of natural killer activity to thyroxine in Graves' disease.

The effect of thyroxine (T4) on natural killer (NK) activity of peripheral blood lymphocytes (PBL) was investigated, using a 4-hr 51Cr release assay, in 18 patients with previously untreated Graves' disease and in 18 controls. NK activity in patients with Graves disease was not significantly different from that in the controls. Normal T4 (NT) and high T4 (HT) medium, free T4 concentrations in which were 1.01 and 16.3 ng/dl, respectively, were used to evaluate the effect of T4 on NK activity. In the controls, NK activity increased in the NT or HT medium compared with that in the control medium at effector to target cell (E:T) ratios of 25 : 1 and 50 : 1. NK activity in the Graves' disease patients, however, did not increase when either the NT or HT medium was used at E : T ratios of 25 : 1 and 50 : 1. These results suggest that patients with Graves' disease have a similar NK activity to the controls but have a defect in the peripheral blood lymphocytes to increase NK activity in response to T4.

Adult↗
PubMed1990

Natural killer and lymphokine-activated killer activities in stomach cancer patients with special emphasis on the effect of 5-fluorouracil, adriamycin and mitomycin-C chemotherapy.

The cytotoxicities of peripheral blood lymphocytes (PBL) and lymphokine-activated killer (LAK) cells were studied to evaluate the effect of chemotherapy on cellular immunity, in 18 patients with unresectable stomach cancer before and after chemotherapy with 5-fluorouracil, adriamycin and mitomycin-C (FAM), and in 21 healthy volunteers. LAK cells were generated in vitro by culturing PBL with 100 U recombinant human interleukin-2 (rH-IL-2)/ml for 72 h. K562 (human myelogenous leukemia), MKN-45 (human stomach adenocarcinoma) and PC-14 (human pulmonary adenocarcinoma) were used as target cells. The cytotoxicity of PBL to K562 and MKN-45 was suppressed in patients with stomach cancer before chemotherapy, compared with that in healthy volunteers (P less than 0.05). The cytotoxicity of LAK cells was significantly higher to all three cell lines tested than that of PBL in both the healthy volunteers and stomach cancer patients (P less than 0.01); however, a lower level of LAK activity was generated in patients with cancer compared to that in the healthy volunteers. FAM therapy did not suppress the cytotoxicities of PBL and LAK cells. The surface markers of PBL and LAK cells were measured, demonstrating that there was no significant change in the percentage of lymphocytes with CD3+, CD4+, CD8+, CD16+ or CD19+ after chemotherapy. The ratios of CD4+ to CD8+ cells in PBL and LAK cells were also not significantly changed after chemotherapy. In the present study, we have demonstrated that the PBL of stomach cancer were defective in generating LAK activity compared to those of controls, but the LAK activity generated from PBL receiving chemotherapy was similar to that from PBL without chemotherapy in stomach cancer patients.

Adult↗
PubMed1989

Enhancement of cytotoxicity of cisplatin in vitro by recombinant human tumor necrosis factor and/or recombinant human interferon-alpha, -beta and -gamma.

This study was conducted to investigate the modulatory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon (rH-IFN)-alpha, -beta and -gamma, either alone or in combination, on the cytotoxicity of cisplatin, using MTT assay, against MKN-45 (human stomach adenocarcinoma). MKN-45 was resistant to rH-TNF even at doses up to 10(3) U/ml. rH-IFN-gamma inhibited the survival of MKN-45 dose-dependently, while rH-IFN-alpha and -beta did not inhibit the survival of MKN-45 even at the highest concentrations tested (10(4) U/ml). Combination of rH-TNF with rH-IFN-alpha, -beta or -gamma did not significantly inhibit the survival of MKN-45, except for a combination of 10 U/ml of rH-TNF and 10(3) U/ml of rH-IFN-gamma (P less than 0.05). Cisplatin inhibited the survival of MKN-45 dose-dependently. By the simultaneous combination of cisplatin with rH-TNF and/or rH-IFN-alpha, -beta or -gamma, cytotoxicity of cisplatin was enhanced and the combination effects were additive. The effects of rH-TNF and rH-IFN-alpha, -beta and -gamma on the modification of cytotoxicity of cisplatin were evaluated in terms of modification index (MI), demonstrating that rH-TNF, rH-IFN-alpha, -beta and -gamma all augmented the cytotoxicity of cisplatin: MI values at 10(3) U/ml of rH-IFN-alpha, -beta and -gamma were 1.4, 1.4 and 2.3, respectively; those at the same concentrations of rH-IFN-alpha, -beta and -gamma in the presence of 10 U/ml of rH-TNF were 3.6, 2.5 and 5.1, respectively. These results demonstrating that the cytotoxicity of cisplatin was enhanced by rH-TNF and/or rH-IFN-alpha, -beta or -gamma suggest that cancer may be more effectively treated with the combination of cisplatin with these biological response modifiers than with cisplatin alone.

Adenocarcinoma↗
PubMed1988

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↗
PubMed1988

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↗