Novel responses of peripheral lymphocytes of cancer patients to chemical induction of sister chromatid exchanges

Sensitivities to sister chromatid exchange (SCE) induction by chemicals of peripheral lymphocytes from 26 cancer patients were estimated under conditions identical to those for healthy humans which had been reported (Cancer Res., 43: 439-442, 1983). The sensitive individual was defined as one whose cells give a mean induced SCE frequency more than 2 standard deviation units above the population mean of induced SCEs in cells from the healthy humans. When cells were treated with 3-amino-1-methyl-5H-pyrido[4, 3-b]indole in the presence of rat liver S9 mix, 8 in 10 stomach cancer patients, 4 in 4 colon cancer patients, 3 in 9 lung cancer patients, 0 in 3 patients bearing other cancers, and 0 in 9 non-cancerous individuals were sensitive. The corresponding frequency of individuals in the healthy population, reported previously, was 1 in 33 persons. Thus, the frequency of sensitive individuals in the combined group of stomach and colon cancer patients was very significantly higher than were frequencies in control groups. Three in 10 patients with stomach cancer and 4 in 16 patients with other cancers were sensitive to induction of SCE by methyl methanesulfonate. Six in these 7 methyl methanesulfonate-sensitive patients were also 3-amino-1-methyl-5H-pyrido[4,3-b]indole sensitive. The frequency of methyl methanesulfonate-sensitive individuals in the healthy populations was 2 in 50. There was no patient who was sensitive to SCE induction by 4-nitroquinoline 1-oxide. The frequency was not significantly different from the healthy population, in which 3 in 50 persons were sensitive. These results suggest that a particular cancer correlates with the sensitivity of peripheral lymphocytes to SCE induction by particular chemicals.     

Sister chromatid exchanges induced in human lymphocytes by cis-diamminedichloroplatinum (II)

Sister chromatid exchanges (SCE) frequency in cultured lymphocytesfrom seven patients with lung cancer receiving cis-Diamminedichloroplatinum(II) (Pt(II)) for chemotherapy was studied. Significantly increasedSCE frequency was observed in all the patients, six of whomreceived intravenous infusion of Pt(II) and one of whom receivedthe agent as an intrapleural infusion. In addition, a dose-dependentincrease in the frequency of SCE was observed in lymphocytesfrom healthy subjects upon exposure to Pt(II) in vitro. The results of the present study revealed that Pt(1l) is a potentinducer of SCE in human lymphocytes in vivo and in vitro. Itthus appears that follow-up study of the long-term survivorswho have been treated with this agent for cancer is necessarybecause of the possible occurrence of secondary neoplasms.     

Sister chromatid exchange frequencies in lymphocytes of oral cancer patients seem to be influenced by drinking habits

Sister chromatid exchange (SCE) values were determined in thelymphocytes of 24 oral cancer patients before therapy and inthe lymphocytes of 24 control persons standardized with respectto sex, age and smoking habits. Oral cancer patients showedsignificantly elevated SCE values (mean 7.82 versus 6.42). Inboth groups the highest SCE values were found in the subgroupswith the highest alcohol consumption. A significant correlationbetween SCE and     

Enhancement of benzo[a]pyrene-induced sister chromatid exchanges in lymphocytes from cigarette smokers occupationally exposed to asbestos

The frequencies of base-line and benzo[a]pyrene [(BP) CAS 50-38-8]-induced sister chromatid exchanges (SCE) were measured in peripheral blood lymphocytes from 22 male asbestos-exposed workers and 10 nonexposed workers of comparable age. A clear association between cigarette smoking and asbestos exposure in the sensitivity of lymphocytes to BP was observed. Among asbestos-exposed workers, lymphocytes from those who smoked cigarettes were significantly more susceptible to the induction of SCE by in vitro exposure to BP (P = .01) than were lymphocytes from nonsmokers. Active smoking elevated the base-line SCE frequency in both asbestos-exposed and nonexposed workers (P = .001), and an interaction between smoking and asbestos in the production of base-line SCE was suggested (P = .07). Asbestos exposure alone was not associated with an enhanced susceptibility to the induction of SCE by BP or with an elevation of base-line SCE. Increased age was associated with an increase in SCE inducibility by BP (P = .01), and a history of smoking was marginally associated with SCE inducibility by BP (P = .07). These findings support the hypothesis that an increased susceptibility of asbestos-exposed individuals to polyaromatic hydrocarbon-induced cancer results from an enhanced sensitivity to the induction of genetic damage rather than to an asbestos-induced differential cellular metabolic capacity.     

芳烃羟化酶与肺癌的关系探讨

目的：研究芳烃羟化酶（ＡＨＨ）与肺癌的关系。方法：采用ＡＨＨ直接测定法检查了肺癌患者４０例、其它癌症患者３２例及健康人４５例血液淋巴细胞中ＡＨＨ的诱导力。结果：１）肺癌组与健康对照组及肿瘤对照组之间构成比均无显著性差异（Ｐ＞０．０５，χ２检验）。２）肺鳞癌组与健康对照组高及低诱导力者之间构成比有显著性差异（Ｐ＜０．０５）；而中、低诱导力者之间构成比无显著性差异（Ｐ＞０．０５）。３）肺腺癌组及其它类型肺癌组与健康对照组之间构成比均无显著性差异（Ｐ＞０．０５）。４）高ＡＨＨ诱导力发生肺癌的相对危险性是低ＡＨＨ诱导力者的６倍。结论：ＡＨＨ的诱导力与肺癌，主要是肺鳞癌有关。作者认为，正常人群中的ＡＨＨ高诱导力者应成为重点预防对象。     

肺癌患者外周血淋巴细胞微核、SCE和染色体畸变的研究

 本文分析观察14例肺癌患者和14例正常健康人外周血淋巴细胞的微核, SCE和染色体畸变。 结果发现肺癌患者的微核率、SCE频率和染色体畸变率均高于正常对照组。 经统计学分析表明两组之间差异显著, 认为染色体不稳定可能是肺癌发生的物质基础。     

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 = 0.842–0.022 x ). 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 chemotherapyinduced thrombocytopenia.     

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.     

Cytogenetic Effects of CPT-11 and Its Active Metabolite, SN-38 on Human Lymphocytes

CPT-11, a new camptothecin analogue, has been demonstrated tobe a promising antineoplastic agent. Late side effects of carcinogenicityand teratogenicity have been unclear from clinical phase I andII trials. In order to elucidate the carcinogenicity and teratogenicityof CPT-11, we have examined the cytogenetic changes in humanperipheral blood lymphocytes induced by CPT-11 and its activemetabolite, SM-38. We have also analyzed the correlation betweenchromosomal damage and acute clinical side effects. When peripheralblood lymphocytes obtained from a healthy donor were exposedto CPT-11, SN-38, cisplatin and mitomycin C, a significant dose-dependentincrease of sister chromatid exchange (SCE) was obtained. TheSCE frequency per cell cultured with 0.244 nM SN-38 was similarto that cultured with 100 nM CPT-11, 300-500 times the concentrationof SN-38. A transient increase in SCE frequency was also observedin the peripheral blood lymphocytes of 11 cancer patients receiving100mg/m² of CPT-11 intravenously, compared with pretreatmentvalues (P= 0.0001). In addition, a significant correlation wasobserved between the frequency of SCE on day 3 and the degreeof decrease in platelet count (P= 0.012). In conclusion, SN-38might possibly have a high risk of mutagenicity and carcinogenicity;and measurement of SCE values in peripheral blood lymphocytesappears to have a potential application in the clinical predictionof chemotherapy-induced side effects.     

Elevated sister chromatid exchange frequencies in the lymphocytes of esophageal cancer patients

Thirty patients with esophageal cancer and 35 healthy controls were studied for spontaneous and mutagen-induced sister chromatid exchange (SCE) frequencies and cellular kinetics in peripheral blood lymphocytes. Some of the patients and controls were tobacco consumers (TC). A mean spontaneous SCE per cell value of 8.36 obtained for the patients was higher significantly (P less than 0.001) compared with a SCE per cell value of 6.74 for the controls. It was noticed that the elevation was significant even when persons in both groups were separated and compared on the basis of tobacco consumption. Among the controls, TC had higher SCE compared with non-tobacco consumers (NTC) (P less than 0.01). Mitomycin C (MMC) was used as a mutagen. No significant difference was observed in MMC-induced rates of SCE between the patients and controls. The cellular kinetics, expressed as average generation time (AGT), also were comparable in both groups. It was concluded that either metabolic stress imposed by the tumor or some clastogenic secretion of malignant cells was responsible for elevated SCE rates in the lymphocytes of the esophageal cancer patients. The disease had no effect on mutagen-induced SCE rates or cellular kinetics in lymphocytes.     

Sister chromatid exchanges (SCE), chromosomal aberrations and micronuclei of cultured peripheral lymphocytes in patients with lung cancer, miners and non-mining workers of the tin mine in Yunnan

Determination of SCE frequency, chromosomal aberration and micronucleus rate of cultured peripheral lymphocytes in 32 patients with lung cancer, 33 miners and 40 non-mining workers in Yunnan Tin Mine was carried out. The results showed that the cancer patients had higher SCE incidence, chromosomal aberration and micronucleus rate, the non-mining workers had the least and miners on an intermediate level. There was a significant difference of SCE, chromosomal aberrations and micronucleus rate between patients and non-mining workers (P less than 0.05-0.01). We also found that miners had a significant higher SCE and chromosomal aberration rate but not micronucleus rate as compared with the non-mining workers. We proposed that some carcinogens present in the Yunnan Tin Mine be responsible for the genetic damages in the miners. Chemical drugs may be considered to contribute to the genetic damage in cancer patients who had a tendency toward an increased SCE, chromosomal aberration and micronucleus rate as compared to the miners, though without reaching a statistical significance. We suggested that combination assay of SCE with chromosomal aberration or micronucleus be an useful index for screening of the high risk population and monitoring the chemical drug prevention of lung cancers in Yunnan Tin Mine.     

Telomere length variation: A potential new telomere biomarker for lung cancer risk

ObjectivesIn this report the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk were examined.Materials and methodsThe study design is case–control. Cases (N = 191) were patients newly diagnosed with histologically confirmed non-small cell lung cancer. Controls (N = 207) were healthy individuals recruited from the same counties as cases and matched to cases on age and gender. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk.ResultsTelomere length variation across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46–14.9] and 0.46 (95% CI: 0.25–0.84) for younger (age ≤ 60) and older (age > 60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% CI: 1.71–39.5) and 0.33 (95% CI: 0.15–0.72) for younger and older individuals, respectively.ConclusionsTLV in blood lymphocytes is significantly associated with lung cancer risk and the associations were modulated by age. TLV in combination with mean telomere length might be useful in identifying high risk population for lung cancer computerized tomography screening.     

Aryl hydrocarbon hydroxylase inducibility in lung cancer patients undergoing radiotherapy

Aryl hydrocarbon hydroxylase (AHH) inducibility was studied in cultured lymphocytes from 21 healthy control subjects and from 15 lung cancer patients selected for radiation therapy. AHH inducibility of the patients was measured prior to, during and at the end of radiation therapy. Four of 15 patients had values comparable to the healthy controls. Cellular DNA and protein measurements of cultured lymphocytes were the same for patients and healthy controls. There was no significant difference in the percentage of lymphoblast formation and percentage of cell survival between the two groups. Radiation therapy reduces the number of lymphocytes in vivo and the amount of lymphoblast formation in vitro. AHH inducibulity is signifcantly lowered by radiation in the patients who had very high inducibility at pre-treatment level. DNA and protein contents of cultured lymphocytes did not change during radiation therapy.     

Genetic etiology of esophageal cancer--III. The spontaneous and mitomycin-C (MMC) induced sister chromatid exchanges (SCE) and chromosome aberrations in cultured lymphocytes from members of "high risk" and "low risk" esophageal cancer families in Linxian County

The spontaneous and mitomycin-c (MMC) induced sister chromatid exchanges (SCE) and chromosome aberrations in cultured lymphocytes from members of "high risk" and "low risk" esophageal cancer families in Linxian County were studied. The results showed that the frequencies of the spontaneous SCE of "high risk" and "low risk" esophageal cancer groups were 7.8 +/- 0.25 and 8.3 +/- 0.25/per cell. There were no difference between these two groups (P greater than 0.5). The frequencies of the SCE induced by MMC in "high risk" and "low risk" esophageal cancer groups were 43.8 +/- 2.4 and 21.6 +/- 1.1/per cell. There were noteworthy difference (P less than 0.001). However, the frequencies of the spontaneous and MMC induced chromosome aberrations in "high risk" cancer families were higher than those of the "low risk" ones.     

肺癌患者染色体稳定性及诱变剂敏感性的研究

目的 探讨细胞染色体不稳定性与肺癌的关系。方法 采用微量全血培养法对２４例经病理证实但未治疗的原发性肺癌患者、２０例非癌性患者和２０名健康志愿者外周血淋巴细胞（ＰＢＬ）进行自发和诱发的染色体畸变和微核检测。结果人肺癌患者ＰＢＬ自发及诱发染色体畸变率和微核率明显高于非癌性肺病患者和健康者;肺癌患者具有较高的染色体畸变率和微核率。肺癌患者染色体稳定性较差。结论 细胞染色体稳定性评价对肺癌的早期诊断、鉴     

小细胞肺癌患者外周血淋巴细胞染色体不稳定性分析

采用低叶酸、高ｐＨ的微量全血细胞培养法，观察２０例小细胞肺癌患者和２０例正常人的外周血淋巴细胞染色体不稳定性，发现实验组染色体畸变率及异常细胞率明显高于对照组（Ｐ＜０．０１），结果表明小细胞肺癌患者存在体细胞染色体不稳定性，人群中部分个体染色体不稳定性增加和癌症的易感性增加有关。     

Immunocompetence in lung cancer patients: analysis of serological and cellular parameters

Some serological (serum immunoglobulins, circulating immune complexes, quantitative assessment of hemolytic complement activity) and cellular (total number of circulating lymphocytes as well their phenotypic and functional characterization) parameters have been analyzed in 42 patients with lung cancer of three hystologic types and in 19 healthy controls to define whether different histologic neoplasms have an impact on the host immune system. As a group, cancer patients showed 1) the presence of circulating immune complexes, in a significant percentage, within all the three groups studied; and 2) a significant reduction of lymphocytes forming E rosette. With regard to cellular immune parameters we noted that 1) T lymphocytes isolated from the peripheral blood lymphocytes (PBL) of patients with lung cancer showed a decreased capacity to express HLA-class II antigens upon phytohemogglutinin (PHA) activation in vitro; 2) PBL from lung cancer, in particular the adenocarcinoma group, failed to proliferate upon stimulation by policlonal mitogens; and 3) the autologous mixed lymphocyte reaction (MLR) of non-T/T-type was impaired in all three groups, whereas the autologous MLR of T/T-type was impaired only in the patients with squamous cell carcinoma and in those with adenocarcinoma, probably as a result of a reduced stimulatory capacity.     

Mutagenicity of gastric juice in patients with chronic gastritis

Mutagenicity of fasting gastric juice from 108 chronic gastritis patients in high- and low-risk areas of stomach cancer was assayed using in vitro SCE test in cultured human lymphocytes and micronucleus test in cultured Chinese hamster V79 cell. The results showed that mutagenicity could be found in this gastric juice. The positive rate of these two tests, SCE/cell, micronucleated cell rate and micronucleus rate were significantly higher in high-risk area than in low-risk area (P less than 0.01). There was a tendency that the mutagenic activity was higher in high pH than in low pH gastric juice and in males than in females. In high-risk area, the mutagenicity of gastric juice was obviously higher in younger than in elder aged group. Because no S9 was added in this test system, the results seem to suggest that the mutagenicity found in the gastric juice of patients with chronic gastritis might be, at least in part, related to direct-acting N-nitroso-compounds synthesized in the stomach.     

Expression and immunogenicity of a tumor-associated antigen, 90K/Mac-2 binding protein,in lung carcinoma

BACKGROUND: The authors attempted to obtain shared proteins among lung carcinoma cells by column chromatographies. A glycoprotein with approximately 500 kDa isolated from QG56 cells showed an identical amino acid sequence to 90K/Mac-2 binding protein (M2BP). This protein has been reported to be highly expressed and to modulate the expression of surface molecules involved in immune responses on cultured cancer cells. Therefore, it would be beneficial for M2BP to be targeted in cancer immunotherapy. METHODS: The authors analyzed the expression of M2BP in lung carcinoma cells and M2BP's immunogenicity as a tumor antigen. Eight cultured lung carcinoma cell lines and 28 tumor tissues from patients with lung carcinoma were examined for the expression of M2BP mRNA and protein. Sera from cancer patients (n = 23) and healthy donors (n = 19) were studied for their reactivity to M2BP peptides by enzyme-linked immunosorbent assay. RESULTS: Seven of the 8 (87.5%) lung carcinoma cell lines and 17 of the 28 (60.7%) tumor tissues expressed high levels of M2BP mRNA. Most of the M2BP mRNA-positive cancer cell lines and tumors also showed M2BP protein expression. The serum levels of antibodies to M2BP were elevated in 30.4% of the patients. In addition, M2BP-specific immunoglobulin G was observed in all patients with anti-M2BP antibodies. CONCLUSIONS: M2BP is highly expressed in lung carcinoma cells and is sufficiently immunogenic to elicit specific immunity to this molecule in patients with lung carcinoma. M2BP is expected to be useful as a tumor marker and a target antigen in cancer immunotherapy.     

Enhanced chromosomal radiosensitivity in peripheral blood lymphocytes of larynx cancer patients

PURPOSE: The chromosomal radiosensitivity in peripheral blood lymphocytes of cancer patients was reported to be higher than that of healthy donors. This effect is especially prominent when aberrations induced in the G2 phase of the cell cycle are analyzed. The aim of our study was to investigate if the G2 aberration frequencies in lymphocytes of patients with larynx cancer are higher than in the case of control individuals. Also, we tested if the frequencies of G2 aberrations correlate with side effects of radiotherapy. METHODS AND MATERIALS: Peripheral blood of 38 patients was collected before the onset of radiotherapy, cultured for 72 h, and irradiated with 2 Gy after 67 h. Lymphocytes of 40 healthy donors were treated in the same way. RESULTS: The spontaneous and radiation-induced aberration frequencies in lymphocytes of patients were on average higher than in those of healthy donors. No statistically significant correlation was observed between aberration frequencies in lymphocytes and the degree of both early and late normal tissue reactions. CONCLUSIONS: The chromosomal radiosensitivity of lymphocytes of patients with larynx cancer may be a marker of cancer predisposition; however, it does not appear to have a predictive value for the risk of developing side effects to radiotherapy.