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M Masutani

Publications and source records attributed to M Masutani.

At least 19 recordsLinked to original sources
PubMed2001

Involvement of poly(ADP-ribose) polymerase in trophoblastic cell differentiation during tumorigenesis.

Poly(ADP-ribose) polymerase (Parp) monitors DNA strand breaks and poly(ADP-ribosyl)ates nuclear proteins using NAD as a substrate. The participation of Parp in DNA damage responses has been demonstrated by recent studies using Parp knockout mice. On the other hand, accumulated evidence has shown that Parp is involved in the regulation of gene expression and cell differentiation. In this study, the role of Parp in tumorigenesis and differentiation was studied with Parp-/- embryonic stem (ES) cells. When Parp+/+, Parp+/-, and Parp-/- ES cells were injected subcutaneously into nude mice, teratocarcinoma-like tumors developed from ES cells. However, only tumors derived from Parp-/- ES cells showed trophoblast giant cells (TGCs) containing single or multiple megalo-nuclei. These TGCs are located in a large blood-lake like hemorrhage. This example suggests that Parp is not essential for tumor formation, however, it is involved in trophoblastic cell differentiation and could consequently affect tumor phenotype.

Animals↗
PubMed2001

Characterization of adriamycin-induced G2 arrest and its abrogation by caffeine in FL-amnion cells with or without p53.

We investigated the effect of Adriamycin on FL-amnion (FL) cells. After treatment with the drug, the cells arrested at G2, but we did not detect an increase in the p21 levels. We established a p53-deficient derivative of these cells, in which G2 arrest also occurred after treatment with Adriamycin, suggesting that the arrest we observed in these cells is independent of the p53 pathway. Low doses of Adriamycin (100-200 ng/ml) induced G2 arrest, while late S-phase arrest was observed at high doses (500-1000 ng/ml) in both FL and p53-deficient FL cells. Accumulation of cyclin B1 was detected only in cells arrested at G2, and not in those arrested at S phase, suggesting that the S-phase checkpoint functioned efficiently even in p53-deficient FL cells. In both cell lines, caffeine-induced activation of CDC2 kinase was detected only in cells arrested at G2 and CDC2 kinase-activated cells died exhibiting features of apoptosis. CDC2 kinase activation was inhibited by cycloheximide. Furthermore, cycloheximide inhibited activation of CDK2:cyclin A, which normally precedes CDC2 kinase activation in caffeine-treated cells. These results suggest that p53 and p21 do not have special roles in the S- and G2-phase checkpoints and that CDK2:cyclin A could be the target of the G2-phase DNA damage checkpoint.

Amnion↗
PubMed2001

Application of hypothermia to autologous stem cell purging.

Autologous stem cell transplantation is used widely after high-dose chemotherapy for treating hematological and other malignancies. Bone marrow harvested for autologous bone marrow transplantation may contain residual malignant cells even when the cancer is judged to be in remission. Attempts to purge marrow of its putative residual malignant cells may delay hemopoietic reconstitution and are of uncertain efficacy. In this report, we demonstrate the possibility of applying hypothermia to autologous stem cell purging. Using clonogenic assay, we compared the surviving fraction of human leukemia (HL60, K562) and human small cell lung cancer (H69) cell lines with that of normal human bone marrow CFU-GM and BFU-E cells after incubation at 4 +/- 0.1 degrees C for 24 and 48 h. Hypothermia decreased the surviving fraction of HL60, H69, and K562 cells. In contrast, the surviving fractions of stem cells were not affected by the temperature shift. The surviving fraction of HL60 cells at 4 degrees C cooling was significantly lower than that at 22 degrees C cooling. These findings suggest that in vitro hypothermia may selectively purge residual malignant cells in stored remission bone marrow and may be applicable before autologous bone marrow transplantation. In addition, the method is very simple and cost effective.

Bone Marrow Purging↗
PubMed2001

Increased susceptibility of poly(ADP-ribose) polymerase-1 knockout mice to nitrosamine carcinogenicity.

The involvement of poly(ADP-ribose) polymerase-1 (Parp-1), one of the poly(ADP-ribose) polymerase family proteins, in genomic stability, DNA repair and cell death triggered by DNA damage has been well documented. However, the potential role of Parp-1 in carcinogenesis has not been well evaluated. In this study the carcinogenic activity of N:-nitrosobis(2-hydroxypropyl)amine (BHP) was studied in Parp-1(-/-) mice, generated by disrupting P:arp-1 gene exon 1. Parp-1(-/-) and Parp-1(+/+) male mice received 0, 250 and 500 p.p.m. BHP in their drinking water for 20 weeks and were then killed. The percentage of animals bearing hemangiomas and hemangiosarcomas in the liver and numbers of tumors per mouse were markedly higher in the Parp-1(-/-) groups given 250 or 500 p.p.m. BHP than in their Parp-1(+/+) counterparts. Hemangiosarcomas developed only in Parp-1(-/-) mice. In the lung the numbers of adenomas per mouse were increased in Parp-1(-/-) mice given BHP at 250 and 500 p.p.m. (P < 0.01) compared with the Parp-1(+/+) case. The results show that susceptibility to BHP is significantly elevated in Parp-1(-/-) mice, thus providing direct evidence that Parp-1 is relevant to carcinogenesis.

Adenocarcinoma↗
PubMed2001

Increased apoptosis associated with depressed type of early intestinal gastric cancer.

Early gastric cancer can be macroscopically classified into elevated and depressed types. To clarify the relationship between macroscopic appearance of early gastric cancer and apoptosis or cell proliferation, formalin-fixed paraffin-embedded tissue specimens of 44 intestinal-type early gastric cancers were investigated by the TUNEL method and immunohistochemical techniques. Diffuse type was excluded in this study. When tissue sections of gastric cancer were vertically classified into the 3 compartments of luminar, intermediate and basal, the apoptosis index (%) was significantly higher in the basal compartment of depressed type (1.76 +/- 2.04, mean +/- SD) than in the basal compartment of elevated type (0.63 +/- 0.81, P = 0.01). In depressed type, the apoptosis index (%) was significantly higher in the basal compartment than in the luminar compartment (0.76 +/- 0.85, P = 0.03). Apoptosis-inducing protein, Bax, was expressed more in each of the compartments of depressed type than in those of elevated type, while there were no significant differences in expression of anti-apoptotic protein, Bcl-2, between the two types. Moreover, the apoptosis index (%) of Bax-positive gastric cancer was significantly higher in the basal compartment (P = 0.03), compared to that of Bax-negative gastric cancer, while there were no significant differences in apoptosis index (%) in any compartment between Bcl-2-positive and Bcl-2-negative gastric cancers. There were no significant differences in Ki-67 expression, either between the two types, or among the compartments of depressed type. These results indicate that increased apoptosis with excessive expression of Bax in the basal compartment is involved in the morphogenesis of the depressed type in intestinal-type early gastric cancer.

Aged↗
PubMed2001

Serum angiotensin I-converting enzyme is reduced in Crohn's disease and ulcerative colitis irrespective of genotype.

OBJECTIVES: Crohn's disease (CD) is recognized to be a vascular endothelial-associated disease. Angiotensin I-converting enzyme (ACE) exists mainly in endothelial cells. There are some reports on serum ACE levels in patients with CD, but the ACE level is still controversial. Recently, genetic control of serum ACE levels by ACE gene polymorphisms (classified as II, ID, and DD) has been suggested. Although we must consider such polymorphisms to elucidate ACE levels in patients with CD, there is no report about this. METHODS: We studied 341 healthy controls (male/female = 178/162), 39 patients with CD (31/8), 43 patients with ulcerative colitis (UC) (22/21) and 19 patients with infectious enterocolitis (8/11). The polymorphism in intron 16 of the ACE gene was examined by PCR. Serum ACE levels were measured by the method of Kasahara. RESULTS: Serum ACE levels in patients with CD and UC were significantly lower than in healthy controls, irrespective of the genotype of ACE (genotype II: CD 7.0+/-2.5 [mean +/- SD], UC 7.1+/-3.3, controls 11.8+/-2.9, genotype ID: CD 9.7+/-4.1, UC 11.4+/-4.6, controls 15.2+/-3.6, genotype DD: CD 13.9+/-5.8, UC 10.7+/-3.6, controls 19.3+/-3.9 IU/L, controls vs CD, UC; p < 0.01, 0.05). However, there was no significant difference in serum ACE levels between CD and UC. CONCLUSIONS: Considering ACE gene polymorphism, serum ACE levels in patients with inflammatory bowel disease are lower than in controls. Serum ACE levels reflect a part of the pathogenesis of inflammatory bowel disease.

Adult↗
PubMed2000

Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma.

BACKGROUND: With the recent development of minimal treatment for early stage gastric carcinoma, identifying specific indicators of the metastatic potential of primary tumors has become more important. Cathepsin B and cathepsin L, both lysosomal cysteine proteases, degrade the extracellular matrix during tumor progression. Although many studies have shown their relation to human cancer progression, little is known about their roles in the early stage. The clinicopathologic significance of cathepsins was therefore studied in early stage gastric carcinoma. METHODS: Expression of both cathepsins was studied immunohistochemically in 51 tissue specimens from gastric carcinomas that invaded the submucosal layer or muscularis propria. The relation between their expression and clinicopathologic factors was analyzed. RESULTS: Both cathepsins were expressed at higher levels in tumors that invaded the muscularis propria than in those within the submucosa (P < 0.05). In addition, tumors with lymphatic invasion showed higher cathepsin B expression than those without it (P < 0.05), whereas tumors with venous invasion showed higher cathepsin L expression than those without it (P < 0.05). No other clinicopathologic factors correlated with expression of either cathepsin. CONCLUSIONS: Tumors with overexpression of cathepsins have powerful potential for invasiveness in the early stage of gastric carcinoma. Moreover, the authors hypothesize that cathepsins may be one of the determinants of the metastatic route. To the authors' knowledge, this is the first report on specific proteases concerning the mode of metastasis, and the results of this study suggest that therapeutic strategies for early stage gastric carcinoma might need to be changed according to the status of cathepsins.

Adult↗
PubMed2000

Transient increase in plasma brain (B-type) natriuretic peptide after percutaneous transluminal coronary angioplasty.

BACKGROUND: Brain (B-type) natriuretic peptide (BNP) is known to be secreted predominantly from the myocardium. Brain natriuretic peptide plasma concentrations have been shown to be markedly increased in patients with acute myocardial infarction; however, plasma BNP response during episodes of myocardial ischemia has not been established. HYPOTHESIS: This study was designed to examine plasma BNP in patients with transient myocardial ischemia induced by inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon. METHODS: Thirty consecutive patients (26 men and 4 women; mean age 61 years) who underwent PTCA, and another 49 patients (39 men and 10 women; mean age 63 years) who underwent diagnostic coronary angiography were enrolled in this study. Serum BNP concentrations were assayed in all patients. RESULTS: Plasma BNP was increased significantly with a peak concentration of 66.1 +/- 65.2 pg/ml 24 h after PTCA. Coronary angiography did not cause plasma BNP increase (immediately before 30.4 +/- 29.0 pg/ml, 24 h after 33.7 +/- 30.6 pg/ml). No significant differences were present in hemodynamic parameters measured immediately before and 24 h after PTCA. CONCLUSION: Plasma BNP is increased by transient myocardial ischemia induced by PTCA.

Adolescent↗
PubMed2000

Vascular endothelial growth factor expression and neovascularisation in non-small cell lung cancer.

Many recent studies have demonstrated that tumour angiogenesis is a potent prognostic factor for various malignant tumours, but this has not been clearly shown in non-small cell lung carcinoma (NSCLC). The purpose of this study was to re-evaluate the prognostic value of MVD associated with VEGF in patients with NSCLC by comparing the immunohistochemical results obtained for CD34 with those obtained for vWf. Microvessel density (MVD) and the expression of vascular endothelial growth factor (VEGF) were investigated in 108 cases of NSCLC by immunohistochemistry. The correlation between von Willebrand factor (vWf) and CD34 staining for MVD was not strong, and vWf staining did not correlate with VEGF expression, but CD34 staining did. Staining for CD34 significantly correlated with survival in adenocarcinoma, distant metastasis and postoperative recurrence, but staining for vWf did not. CD34 was more sensitive and specific than vWf for staining endothelial cells associated with VEGF expression. It is suggested that research on neovascularisation should be investigated on every histological subtype or should focus on the early stages of NSCLC which are not under the influence of a variety of complications facilitating tumour neovascularisation.

Aged↗
PubMed2000

The response of Parp knockout mice against DNA damaging agents.

Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have identified the various roles of Parp in cellular responses to DNA damage. The partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant mice indicates the participation of Parp in the repair of DNA strand break. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage induced by reactive oxygen species implicates the contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to the lethal effects of gamma-irradiation. Parp(-/-) mice show more severe villous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(-/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the glandular stomach and other tissues, such as the testes, after gamma-irradiation. Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the spleen is probably the underlying mechanism of hemorrhagic tendency in various tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity could contribute to post-irradiation tissue hemorrhage.

Alkylating Agents↗
PubMed2000

[Clinical characteristics of ventricular tachycardia and ventricular fibrillation in exercise stress testing].

OBJECTIVES: Ventricular tachycardia (VT) and ventricular fibrillation (Vf) induced in exercise stress testing should be treated urgently, although the occurrence of arrhythmia is rare. The conditions for the onset of arrhythmia and the clinical characteristics of VT and Vf patients in exercise stress testing were studied. METHODS: Fifty-nine patients (mean age 54 +/- 17 years, 41 males, 18 females) with VT (succession of 3 or more ventricular premature beats) or Vf induced in exercise stress testing were selected from 7,594 patients with consecutive treadmill stress testing in our hospital from January 1993 to February 1998. RESULTS: The incidence of exercise-induced VT or Vf was 0.8%, and there were no fatal accidents in all tests. Among the 59 patients with exercise-induced VT or Vf, 52 patients had non-sustained VT, 5 had sustained VT, and 2 had Vf. Of the 59 patients, 23 had rhythm or conduction disturbances, 14 had coronary artery disease, 13 had cardiomyopathy, and 9 had valvular heart disease. The VT or Vf incidence in coronary artery disease was 0.2%, and in valvular heart disease was 10.8%. VT or Vf occurred at over 80% of maximum heart rate exercise intensity in 40 patients, including 4 with sustained VT and 2 with Vf, of the 59 patients. Also, in 9 VT patients including the 4 sustained VT patients, VT occurred in the exercise recovery period within 2 min after the exercise. Although VT disappeared spontaneously in 52 non-sustained VT and 3 sustained VT patients, intravenous injection of lidocaine was needed in 2 sustained VT patients and direct current defibrillator was needed in 2 Vf patients. Furthermore, only one non-cardiac death was observed in the follow-up period of average 42 months. CONCLUSIONS: Our results showed clinical characteristics and incidence of VT or Vf similar to past reports. Furthermore, all sustained VT and Vf patients, who should be treated urgently, had a past history of ventricular premature beats or VT. Our data suggest that VT and Vf could occur during the recovery period, especially in patients with documented ventricular tachyarrhythmias when the stress intensity has reached the critical level in the exercise tolerance test.

Aged↗
PubMed1999

Syncytiotrophoblastic giant cells in teratocarcinoma-like tumors derived from Parp-disrupted mouse embryonic stem cells.

The enzyme poly(ADP-ribose) polymerase (Parp) catalyzes poly(ADP-ribosyl)ation reaction and is involved in DNA repair and cell death induction upon DNA damages. Meanwhile, poly(ADP-ribosyl)ation of chromosome-associated proteins is suggested to be implicated in the regulation of gene expression and cellular differentiation, both of which are important in tumorigenesis. To investigate directly the role of Parp deficiency in tumorigenicity and differentiation of embryonic stem (ES) cells during tumor formation, studies were conducted by using wild-type J1 (Parp(+/+)) ES cells and Parp(+/-) and Parp(-/-) ES clones generated by disrupting Parp exon 1. These ES cells, irrespective of the Parp genotype, produced tumors phenotypically similar to teratocarcinoma when injected s.c. into nude mice. Remarkably, all tumors derived from Parp(-/-) clones contained syncytiotrophoblastic giant cells (STGCs), which possess single or multiple megalo-nuclei. The STGCs were present within large areas of intratumoral hemorrhage. In contrast, neither STGC nor hemorrhage was observed in tumors of both wild-type J1 cells and Parp(+/-) clones. Electron microscopic examination showed that the STGCs possess microvilli on the cell surface and contained secretory granules in the cytoplasm. Furthermore, the cytoplasms of STGCs were strongly stained with antibody against mouse prolactin, which could similarly stain trophoblasts in placenta. These morphological and histochemical features indicate that the STGCs in teratocarcinoma-like tumors derived from Parp(-/-) clones belong to the trophoblast cell lineage. Our findings thus suggest that differentiation of ES cells into STGCs was possibly induced by the lack of Parp during the development of teratocarcinoma.

Animals↗
PubMed1999

Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro.

It has been suggested that DNA-dependent protein kinase (DNA-PK) is a central component of DNA double-strand-break repair. The mechanism of DNA-PK action, however, has not been fully understood. Poly(ADP-ribose) polymerase (PARP) is another nuclear enzyme which has high affinity to DNA ends. In this study, we analysed the interaction between these two enzymes. First, DNA-PK was found to suppress the PARP activity and alters the pattern of poly(ADP-ribosyl)ation. Although DNA-PK phosphorylates PARP in a DNA-dependent manner, this modification is unlikely to be responsible for the suppression of PARP activity, since this suppression occurs even in the absence of ATP. Conversely, PARP was found to ADP-ribosylate DNA-PK in vitro. However, the auto-phosphorylation activity of DNA-PK was not influenced by this modification. In a competitive electrophoretic mobility shift assay, Ku 70/80 complex, the DNA binding component of DNA-PK, was found to have higher affinity to a short fragment of DNA than does PARP. Furthermore, co-immunoprecipitation analysis suggested direct or close association between Ku and PARP. Thus, DNA-PK suppresses PARP activity, probably through direct binding and/or sequestration of DNA-ends which serve as an important stimulator for both enzymes.

Antigens, Nuclear↗
PubMed1999

Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes.

Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp-/-) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced beta-cell damage in vivo. The wild-type (Parp+/+) mice showed significant increases in blood glucose concentration from 129 mg/dl to 218, 370, 477, and 452 mg/dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ/kg body weight. In contrast, the concentration of blood glucose in Parp-/- mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp+/+ mice on day 1, with subsequent progressive islet atrophy and loss of functional beta cells from day 7. In contrast, the extent of islet beta-cell death and dysfunction was markedly less in Parp-/- mice. Our findings clearly implicate Parp activation in islet beta-cell damage and glucose intolerance induced by STZ in vivo.

Animals↗
PubMed1999

Effect of Tween-80 on cell killing by etoposide in human lung adenocarcinoma cells.

PURPOSE: The non-ionic detergent Tween-80, a surface-active agent, has been shown to modulate the cytocidal effect of certain antitumor agents. In the present study, we sought to determine whether or not Tween-80 could enhance the antitumor effect of etoposide (VP16) in human lung cancer cells in vitro. METHODS: Survival fractions were measured by growth inhibiton assays of PC14, H69, KB, and PC14/CDDP (the corresponding cisplatin-resistant subline of PC14) cells. An in vitro clonogenic assay of PC14 and PC14/CDDP cells was undertaken after incubation for 10-12 days in RPMI-1640 medium with 20% fetal calf serum and 1.72% methyl cellulose, plus continuous exposure to VP16 with Tween-80. We also investigated the direct toxicity of Tween-80 to PC14 and PC14/CDDP cells using a clonal assay. The intracellular accumulation of VP16 was further analyzed using [3H]VP16 in PC14, PC14/CDDP, A549, KB and H69 cells, and compared with that of daunorubicin (DNR), a hydrophilic anti-cancer agent, using [3H]DNR in PC14, A549 and KB cells. RESULTS: It was found that PC14/CDDP had collateral sensitivity to VP16 and Tween-80 markedly enhanced the killing effect of VP16 not only of PC14 cells but also of PC14/CDDP cells while exerting little cytotoxic effect. Moreover, Tween-80 increased the intracellular accumulation of VP16 in PC14, PC14/CDDP and A549 cells, and not in KB and H69 cells. Tween-80 did not increase the intracellular DNR levels in PC14, A549 and KB cells. CONCLUSIONS: Tween-80 was shown to potentiate the cytotoxicity of VP16 against several human lung adenocarcinoma cells by increasing the accumulation of VP16 in vitro. Tween-80-mediated sensitization of lung adenocarcinoma cells to VP16 is considered to be related to both the characteristics of the cell membrane in adenocarcinoma cells and the lipotropic properties of VP16. These results suggest that this combination might have the potential to improve the therapeutic index of VP16 in human lung adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Isolation and cloning of rat poly(ADP-ribose) glycohydrolase: presence of a potential nuclear export signal conserved in mammalian orthologs.

Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme of poly(ADP-ribose) degradation. To understand its structure-and-function relationship, we purified Parg from rat testis 9,740-fold using an improved affinity column; the purified product was a 60 kDa protein. Based on the determined sequences of three peptide fragments, degenerated primers were synthesized and a Parg cDNA comprising 3,974 nucleotides, encoding a 109 kDa protein, was isolated. The 60 kDa Parg purified from rat testes corresponded to the C-terminal half of the 109 kDa deduced peptide. When recombinant rat Parg was expressed as a glutathione S-transferase fusion protein in Escherichia coli, Parg activity was observed for the full-length and C-terminal half proteins but not in for the N-terminal half protein. Taken together, these data indicate that the catalytic domain of Parg is located in the C-terminal half. Further, we newly identified the presence of a potential nuclear export signal in the N-terminal half in addition to the previously reported nuclear localization signals in rat and other mammalian Pargs. Northern blot analysis showed the ubiquitous expression of a single 4.0 kb Parg mRNA in various rat tissues. The findings suggest that the 60 kDa Parg is produced by post-transcriptional processing.

Amino Acid Sequence↗
PubMed1999

Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer.

PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)-based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area-based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC. PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 x (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m(2) was given intravenously on days 1, 2, and 3. Patients aged >/= 70 years old with a performance status of 0 to 2 were eligible. RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%. CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.

Aged↗