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The use of general anesthesia (GA) with inhalational anesthetics for breast cancer surgery may be associated with breast cancer recurrence and increased mortality due to the immunosuppressive effects of these drugs. Less-immunosuppressive anesthetic techniques may reduce breast cancer recurrence. We evaluated the feasibility, safety, and efficacy of outpatient breast-conserving surgery (BCS) for breast cancer in a breast clinic in terms of the anesthetic technique used, complications occurring, recurrence, and survival. Methods: The sample comprised 456 consecutive patients with stage 0–III breast cancer who underwent BCS/axillary lymph node (ALN) management using local and intravenous anesthesia and/or sedation between May 2008 and January 2020. Most patients received adjuvant chemotherapy and/or endocrine therapy and radiotherapy after surgery. Patient outcomes were evaluated retrospectively. Results:All patients recovered and were discharged after resting for 3–4 h postoperatively. No procedure-related severe complication or death occurred. Sixty-four complications (14.0%) were observed: 14 wound infections, 17 hematomas, and 33 axillary lymphoceles. The median follow-up period was 2259 days (range, 9–4190 days), during which disease recurrence was observed in 25 (5.4%) patients. The overall survival and breast cancer–specific survival rates were 92.3% and 94.7%, respectively. Conclusions:Outpatient surgery for breast cancer involving BCS and ALN management under local and intravenous anesthesia and/or sedation can be performed safely, without serious complication or death. Less-immunosuppressive anesthetic techniques with spontaneous breathing may reduce the recurrence of breast cancer and improve survival relative to GA.

A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and therapeutic outcome. Even though apoptosis is thought to play a major role in anticancer therapy, the clinical relevance of induction of apoptosis remains uncertain, particularly in solid tumors. Induction of apoptosis by anticancer agents has been shown to correlate with tumor response, however, nonapoptotic forms of cell death, such as autophagy and extrinsic senescence, have also been shown to contribute to the overall tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis, and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various concentrations of anticancer agents. Apoptosis-resistant cells and transduction pathways which inhibit apoptosis can induce nonapoptotic mechanisms of cell death and senescence, thereby preserving the antitumor effect of some anticancer agents. Heterogeneic antitumor responses include various cell types of cell death, depending on the degree of cellular or DNA damage incurred by cancer cells. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the clinical significance of apoptosis, as well as the potential contribution of other types of cell death to overall tumor sensitivity in the hopes that new therapeutic strategies might follow.

Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy. Four human breast cancer cell lines were examined, and the effects of antisense (AS) Bcl-2and AS Bcl-xLphosphorothioate oligodeoxynucleotides (ODNs) on chemosensitivity were tested in vitroand in vivo. Chemosensitivity was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, and the antitumor effect was assessed in vivoby the success of xenograft transplantation into athymic mice. Treatment with AS Bcl-2and Bcl-xLODNs resulted in a sequence-specific decrease in protein expression, compared with controls. Treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2increased chemosensitivity to doxorubicin (DOX), mitomycin C (MMC), paclitaxel (TXL), and docetaxel (TXT). Transfection of the Bcl-2gene into MDA-MB-453 cells decreased sensitivity to DOX and MMC. Treatment of MDA-MB-231, BT-474, and ZR-75-1 cells with AS Bcl-xLincreased chemosensitivity to DOX, MMC and taxanes to a smaller extent than AS Bcl-2. This occurred in the setting of increased Bax and cleaved poly(ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2ODNs induced splenomegaly in association with increased serum IL-12, which was attenuated by methylation of the CpG motifs of AS Bcl-2; however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Bcl-2 and Bcl-xL, to a smaller extent, are major determinants of chemosensitivity in breast cancer cells. Targeted therapy against Bcl-2 protein with the use of AS ODNs might enhance the effects of chemotherapy in patients with breast cancer.

Introduction Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy.Methods Four human breast cancer cell lines were examined, and the effects of antisense (AS) Bcl-2 and AS Bcl-xL phosphorothioate oligodeoxynucleotides (ODNs) on chemosensitivity were tested in vitro and in vivo. Chemosensitivity was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, and the antitumor effect was assessed in vivo by the success of xenograft transplantation into athymic mice.Results Treatment with AS Bcl-2 and Bcl-xL ODNs resulted in a sequence-specific decrease in protein expression, compared with controls. Treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2 increased chemosensitivity to doxorubicin (DOX), mitomycin C (MMC), paclitaxel (TXL), and docetaxel (TXT). Transfection of the Bcl-2 gene into MDA-MB-453 cells decreased sensitivity to DOX and MMC. Treatment of MDA-MB-231, BT-474, and ZR-75-1 cells with AS Bcl-xL increased chemosensitivity to DOX, MMC and taxanes to a smaller extent than AS Bcl-2. This occurred in the setting of increased Bax and cleaved poly(ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, which was attenuated by methylation of the CpG motifs of AS Bcl-2; however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Bcl-2 and Bcl-xL, to a smaller extent, are major determinants of chemosensitivity in breast cancer cells.Conclusion Targeted therapy against Bcl-2 protein with the use of AS ODNs might enhance the effects of chemotherapy in patients with breast cancer.

Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), through phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not only the inflammatory reaction, but also by an increase in anti-inflammatory factors such as IL-10, TGF-_, and prostaglandin E2 (PGE2), leading to an anti-inflammatory situation, whereby apoptosis contributes to a non-inflammatory response. However, because PS and PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with the PS receptor on macrophages, which promotes an anti-inflammatory response to macrophages that may lead to immune escape. The sPS derived from cancer cells also reacts with the PSR on the cancer cells to produce IL-10, TGF-_, and PGE2, which can cause suppression of antitumor immunity through the anti-inflammatory response to macrophages, which produces tumor-associated macrophages. Furthermore, sPS and TGF-_ inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs. The potential roles of PS and PSR in cancer cells and macrophages in immune escape mediated by sPS and anti-inflammatory factors are discussed, which may explain their dual regulation of anti- and pro-inflammatory responses during tumor progression.

Neoadjuvant chemotherapy was initially used only as treatment for locally advanced breast cancer. However, because breast cancer is considered to be a systemic disease in which distant micrometastases are already present at the time of the initial diagnosis, primary systemic therapy may be beneficial in the eradication of these micrometastatic lesions. Despite the fact that no survival benefit of neoadjuvant chemotherapy over adjuvant chemotherapy has yet been demonstrated, the clinical indication for neoadjuvant chemotherapy is being extended not only to stage T3/4 tumors but also to some stage T1/2 operable breast cancers. The current clinical benefits of the use of neoadjuvant chemotherapy are that (1) the safety of neoadjuvant chemotherapy is comparable with that of adjuvant chemotherapy, (2) neoadjuvant chemotherapy increases the possibility of the use of breast-conserving surgery, and (3) pathologic complete response may be a predictive indicator of better survival. Importantly, the response to neoadjuvant chemotherapy in vivo could provide a useful prediction of prognosis and help define strategies for an individual patient's future treatment with alternative chemotherapy regimens or molecular-targeting agents. Furthermore, the discovery of predictive markers for tumor response to neoadjuvant chemotherapy through the analysis of complementary DNA microarrays and proteomics may also help facilitate individualized chemotherapy, particularly by improving survival in patients with breast cancer with a poor prognosis. Herein we review the current status and future role of neoadjuvant chemotherapy in operable breast cancer in terms of its survival benefit and the potential for the individualization of adjuvant therapy for these patients.

Autocrine and paracrine growth mediated by the platelet‐derived growth factor (PDGF)/PDGF receptor (PDGFR)‐signaling pathway plays an important role in the progression of solid tumors. The authors assessed the effect of STI571 on the tumor growth of gastric carcinoma in combination with 5‐fluorouracil (5‐FU) or paclitaxel targeting the PDGF/PDGFR‐signaling pathway.In MKN‐45 gastric carcinoma cells, the cytotoxic effect was evaluated by 3‐(4,5 dimethiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay, and the in vivo antitumor effect was evaluated in a nude mouse xenograft. Both STI571 and an antitumor drug were administered intraperitoneally. Gene expression was assessed by Western blot analysis and immunohistochemical staining. Apoptotic cell death was evaluated by the terminal deoxyuridine triphosphate‐biotin nick‐end labeling assay, and tumor angiogenesis was evaluated by microvessel density analysis.Treatment with STI571 alone was not effective in vitro, as assessed by a 50% inhibitory concentration value of 24.3 μM. Combination treatment with STI571 and 5‐FU or paclitaxel enhanced the cytotoxic effect somewhat when the concentration of STI571 was increased to 10 μM. Combination treatment with STI571 and 5‐FU or paclitaxel enhanced the antitumor effect of the antitumor drug significantly in vivo. The enhanced antitumor effect was associated with increased apoptotic cell death and inhibition of tumor angiogenesis. Treatment with STI571 down‐regulated the expression of PDGF‐BB and PDGFR‐β in tumor cells and decreased the production of phosphorylated PDGFR‐β and phosphorylated Akt. Furthermore, treatment with STI571 inhibited the expression of PDGFR‐β in stromal cells.STI571 was an effective chemosensitizer of antitumor drugs, such as 5‐FU and paclitaxel for gastric carcinoma, targeting the PDGF/PDGFR‐signaling pathway of tumor cells and stromal cells in disease progression and angiogenesis. Cancer 2005. © 2005 American Cancer Society.

Because the overexpression of HER‐2 and Bcl‐2 is associated with resistance to tamoxifen (TAM), the authors examined the effect of antisense (AS) Bcl‐2 on sensitivity to TAM compared with the effect of trastuzumab on sensitivity to TAM in breast carcinoma cell lines.Drug sensitivity was assessed in vitro using a [3‐4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay with the breast carcinoma cell lines ZR‐75‐1, MDA‐MB‐453, and BT‐474. AS Bcl‐2 18‐mer phosphorothioate oligonucleotide was applied. Apoptotic cell death was assessed with the terminal deoxynucleotidyl transferase‐mediated biotinylated UTP nick‐end labeling method, and gene expression was evaluated with Western blot analysis.The expression of Bcl‐2 was identified in ZR‐75‐1 and BT‐474 cells and, to a lesser extent, in MDA‐MB‐453 cells. Overexpression of HER‐2 was identified in BT‐474 cells, and moderate expression was identified in MDA‐MB‐453 and ZR‐75‐1 cells. Combination treatment with trastuzumab or AS Bcl‐2 enhanced TAM sensitivity in ZR‐75‐1 cells, which showed 50% inhibitory concentration (IC50) values of 0.9 μM (7.2‐fold increase) and 0.5 μM (13.0‐fold), respectively. Combination treatment with trastuzumab or AS Bcl‐2 slightly enhanced TAM sensitivity of BT‐474 cells, with IC50 values of 3.0 μM (1.3‐fold) and 1.5 μM (2.6‐fold), respectively. The sensitivity of MDA‐MB‐453 cells to TAM was not enhanced by combination with trastuzumab or AS Bcl‐2. Modulation of TAM sensitivity by AS Bcl‐2 was superior to modulation by trastuzumab in HER‐2‐expressing and Bcl‐2‐expressing breast carcinoma cells. Enhanced sensitivity in combination with AS Bcl‐2 was associated with down‐regulation of Bcl‐2 and pAkt, which was correlated with the induction of Bax and caspase‐3, leading to apoptosis.AS Bcl‐2 appeared to be superior to trastuzumab with respect to regulating the signal‐transduction pathways involved in breast carcinoma cells. Cancer 2005. © 2005 American Cancer Society.

Over the past two decades, the role of apoptosis in the cytotoxicity of anticancer drugs has become clear. Apoptosis may occur via a death receptor‐dependent (extrinsic) or independent (intrinsic or mitochondrial) pathway. Mitochondria play a central role in cell death in response to DNA damage, and mediate the interaction(s) of various cytoplasmic organelles, including the endoplasmic reticulum, Golgi apparatus, and lysosomes. The mitochondrial pathway of cell death is mediated by Bcl‐2 family proteins, a group of antiapoptotic and proapoptotic proteins that regulate the passage of small molecules, such as cytochrome c, Smac/Diablo, and apoptosis‐inducing factor, which activates caspase cascades, through the mitochondrial transition pore. In addition, apoptosis can induce autophagic cell death via crosstalk between the two pathways upon treatment with anticancer drugs. The current review focused on recent advances surrounding the mechanism(s) of cell death induced by anticancer agents and discussed potential molecular targets for enhancing the chemotherapeutic effect(s) of anticancer agents. Cancer 2005. © 2005 American Cancer Society.

Bcl‐2 protein plays a critical role in inhibiting anticancer drug‐induced apoptosis, which is mediated by a mitochondria‐dependent pathway that controls the release of cytochrome c from mitochondria through anion channels. Constitutive overexpression of Bcl‐2 or unchanged expression after treatment with anticancer drugs confers drug resistance not only to hematologic malignancies but also to solid tumors. The down‐regulation of Bcl‐2 protein by the antisense (AS) Bcl‐2 (oblimesen sodium) may be a useful method for targeting the antiapoptotic protein and thereby increasing the chemotherapeutic effect of anticancer drugs. Several randomized, controlled, Phase III trials have compared standard chemotherapy with a combination of AS Bcl‐2 and standard chemotherapy for the treatment of patients with chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, and nonsmall cell lung carcinoma. Nonrandomized clinical trials and preclinical evaluations of AS Bcl‐2 also are underway for patients with other malignancies. Here, the authors review the current clinical and preclinical evaluations of AS Bcl‐2 and discuss its potential to act as a chemosensitizer and to enhance the therapeutic effect of cancer chemotherapy. Cancer 2004. © 2004 American Cancer Society.

Because bcl‐2 is a critical factor for anticancer drug‐induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl‐2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma.AS bcl‐2 was used with 18‐mer phosphorothiated oligonucleotides in the MKN‐45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl‐thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick‐end labeling assay. AS bcl‐2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week.bcl‐2 was down‐regulated to 60% of its initial value after treatment with 1.0 μM AS bcl‐2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3–4‐fold when used in combination with AS bcl‐2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly‐adenosine diphosphate (ADP‐ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl‐2. Down‐regulation of bcl‐2 was observed on Day 4 after the treatment with AS bcl‐2.Combination treatment with AS bcl‐2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma. Cancer 2004. © 2004 American Cancer Society.

Despite the fact that expression of Fas ligand (FasL) in cytotoxic T lymphocytes (CTLs) and in natural killer (NK) cells plays an important role in Fas-mediated tumor killing, During tumor progression FasL-expressing tumor cells are involved in counterattacking to kill tumor-infiltrating lymphocytes (TILs). Soluble FasL levels also increase with tumor progression in solid tumors, and this increase inhibits Fas-mediated tumor killing by CTLs and NK cells. The increased expression of FasL in tumor cells is associated with decreased expression of Fas; and the promoter region of the FASL gene is regulated by transcription factors, such as neuronal factor κB (NF-κB) and AP-1, in the tumor microenvironment. Although the ratio of FasL expression to Fas expression in tumor cells is not strongly related to the induction of apoptosis in TILs, increased expression of FasL is associated with decreased Fas levels in tumor cells that can escape immune surveillance and facilitate tumor progression and metastasis. Transforming growth factor β (TGF-β) is a potent growth inhibitor and has tumor-suppressing activity in the early phases of carcinogenesis. During subsequent tumor progression, the increased secretion of TGF-β by both tumor cells and, in a paracrine fashion, stromal cells, is involved in the enhancement of tumor invasion and metastasis accompanied by immunosuppression. Herein, the authors review the clinical significance of FasL and TGF-β expression patterns as features of immune privilege accompanying tumor progression in the tumor microenvironment. Potential strategies for identifying which molecules can serve as targets for effective antitumor therapy also are discussed. Cancer 2004. © 2004 American Cancer Society.

Recent advances in molecular biology have led to the development of selective molecular targeting agents for genes involved in cell proliferation, apoptosis, and angiogenesis in cancer cells. The current success of molecular targeting therapy is shown by: imatinib mesylate (STI571, Gleevec), targeted to the Bcr/Abl fusion protein derived from a translocation between chromosomes 9 and 22 in chronic myelogenous leukemia; rituximab (Rituxan), a monoclonal antibody to CD20 used in non-Hodgkin’s lymphoma; trastuzumab (Herceptin), a chimeric monoclonal antibody to HER-2 used in breast cancer; and gefinitib (ZD1839, Irresa), a tyrosine kinase inhibitor of the epidermal growth factor receptor used in non-small cell lung cancer. The superior therapeutic efficacy of these molecular targeting agents over traditional chemotherapy has been shown by the survival benefit achieved for patients with advanced or recurrent cancers. Although the precise molecular mechanisms by which these agents produce or enhance an antitumor effect, alone or in combination with anticancer drugs, are not known, the specific inhibition of target genes critically involved in tumor progression and metastasis by the agent is clear. However, further studies to determine which patient groups and anticancer drugs are appropriate for combination therapy with these molecular targeting agents are needed. Herein, we discuss the current status and potential for overcoming drug resistance in solid tumors and focus on the differential features of the tumor microenvironment in solid and hematologic malignancies.

To analyze the clinical efficacy of a protracted infusion of low-dose 5-fluorouracil (5-FU) and cisplatin (CDDP), a phase II study was performed in 36 patients with advanced gastric cancer. The treatment schedule of the low-dose administration of 5-FU and CDDP (FP) was a continuous infusion of 5-FU (250mg/m2) for 28 consecu-tive days and a drip infusion of CDDP (3.5mg/m2) for 5 consecutive days, followed by a 2-day interval each week in one cycle. The overall response rate was 47.2%. Of importance, the improvement in quality of life assessed by performance status (PS) and oral intake was 13.9% and 33.3%, respectively. The toxicity in low-dose FP treatment was less than grade 2, including gastrointestinal toxicities and bone marrow suppression, and this was tolerable during the treatment. The median survival time (MST) and 1-year survival rate were 8 months and 36.2%, respectively. In a pharmacokinetic analysis following the protracted infusion of low-dose FP, the plasma concentrations of 5-FU and CDDP were increased to about 120–130ng/ml and 0.3–0.5μg/ml on day 21 after the treatment, respectively. The plasma concentrations of 5-FU and CDDP were not significantly different between responders and non-responders. The tumor response to low-dose FP treatment was associated with the induction of apoptotic cell death and with the overexpression of apoptosis-related genes, such as Baxand Bcl-Xs, in cancer cells. These results indicate that the protracted infusion of low-dose FP could be a useful regimen for patients with advanced gastric cancer, in terms of the high response rate and low toxi-city, possibly leading to the prolongation of survival and improvement in the quality of life.

Irinotecan, 7-ethyl-10-[4-(I-piperidino)-1-piperidino] carbonyloxycamptothecin, (CPT-11) resistance was overcome by using a biscoclaurine alkaloid, cepharanthine, in CPT-11- and multidrug-resistant 50MT-1 cells. 50MT-1 cells were established from a mouse breast-cancer cell line, FM3A, by subjecting the cells to a low dose of CPT-11 continuously. 50MT-1 cells exhibited resistance to CPT-11 (40-fold in colony-formation assay) and to other drugs such as doxorubicin (11.7-fold) and etoposide (VP-16) (16.8-fold). The plasma trans-membrane potential was lower in 50MT-1 cells than in FM3A cells, although there were no differences in expressions of P-glycoprotein and of DNA topoisomerase-I and -II proteins. The lower membrane potential in 50MT-1 cells was augmented by co-treatment with a non-toxic dose of cepharanthine. CPT-11 resistance in 50MT-1 cells was overcome (5.0- to 1.4-fold, 6-hr exposure) by the co-treatment with cepharanthine through increasing intracellular accumulation of CPT-11. Resistance to doxorubicin and VP-16 was also overcome by cepharanthine treatment (2.5- to 0.69-fold and 4.2- to 1.4-fold respectively). We conclude that the modification of plasma trans-membrane potential by cepharanthine should be effective in overcoming CPT-11 and multidrug resistance in 50MT-1 cells. Int. J. Cancer, 72:295–300, 1997. © 1997 Wiley-Liss, Inc.

Abstract: P-glycoprotein is a transmembrane protein with increased drug efflux from resistant cells, which is encoded by the MDR1 gene. An overexpression of P-glycoprotein has been reported to correlate with the degree of resistance to anticancer agents, especially to adriamycin. In this study, the expression of P-glycoprotein was analyzed immunohistochemically by using a monoclonal antibody, MRK16 against P-glycoprotein in 18 fresh human tumors. The expression of P-glycoprotein was detected in eight (44 per cent) tumor specimens out of 18 patients. Although six (75.0 per cent) of the 8 P-glycoprotein positive tumors were resistant to adriamycin, the other two tumors showed clinical responses. Furthermore, five (50.0 per cent) of the 10 P-glycoprotein negative tumors exhibited positive clinical responses. These results suggest that P-glycoprotein expression may not be a useful marker to predict intrinsic resistance to adriamycin in fresh human tumors.

We review herein current work on the cytotoxic and cellular actions of two classes of inhibitors of DNA topoisomerase II: one represented by etoposide and teniposide, which stabilize DNA-protein complexes, and another represented by merbarone and aclarubicin, which do not stabilize such complexes. We discuss current concepts of protooncogene activation and cell cycle perturbations by some of these inhibitors and summarize recent findings of novel actions of the latter compounds in tumor cells that express a mutant topoisomerase II.

Abstract: In order to assess the usefulness of chemosensitivity tests in the treatment of colorectal cancer, 71 tumor specimens were tested for chemosensitivity in the following assays: nude mouse isotope assay (NMIA), subrenal capsule assay (SRCA), human tumor clonogenic assay (HTCA) and adenosine triphosphate inhibition assay (ATPA). The agents examined were: mitomycin C (MMC), 5-fluorouracil (5-FU), cyclophosphamide (CPM), adriamycin (ADM) and cis-diamminedichloroplatinum (CDDP). The evaluability rates were 90.8, 93.9 and 92.3 per cent in NMIA, SRCA and ATPA, respectively, but only 42.9 per cent in HTCA. The tumor response rates were 50.8, 45.2, 16.7 and 33.3 per cent in NMIA, SRCA, HTCA and ATPA, respectively. Individual drug sensitivity rates differed among all 4 assays, ranging from 0 to 33.3 per cent. In the arbitrary judgment of the 4 assays, the most sensitive agent was CDDP, followed by CPM, ADM, 5-FU and MMC. In the prospective study, predictive accuracy rates of the clinical responses were 81.3 66.7, 100, 100 and 76.5 per cent in NMIA, SRCA, HTCA, ATPA and the arbitrary judgment, respectively. A significant correlation between the survival time and the results of SRCA was detected retrospectively. These results suggested that colorectal cancer might not be completely resistant to anticancer agents, and that chemosensitivity tests might be useful in the individual therapy of colorectal cancer patients.

Abstract: A four day subrenal capsule assay was investigated in order to determine its ability to clinically predict tumor chemosensitivity. To establish more objective and accurate evaluation criteria, a histological assessment and measurement of the DNA and protein content of excised tumor implants was conducted in ddY mice. The histological studies provided qualitative results concerning the percentage of cancer cells in the xenograft, the number of mitoses, the amount of necrosis, and the extent of lymphocytic infiltration. The DNA content was measured by a modified version of the Schmidt-Thannhauser-Schneider method and the protein content was estimated using the Bio-Rad protein assay. The percentage of cancer cells in the xenograft correlated poorly with the relative increase in tumor size, weight and the percentage inhibition of DNA/protein (per cent DNA/protein), however, the per cent DNA/protein correlated well with the clinical effects in 85.7 per cent of the tumors studied. Moreover, the histological assessment information was only consistent with those results obtained for per cent DNA/protein in the control group.

Abstract: In order to predict natural resistance to Adriamycin (ADM), the amplification of multidrug resistance gene 1 (MDR1) was investigated in 50 human cancer specimens using Southern blot analysis. Genomic DNA was extracted from both human solid tumors and adjacent normal tissues for the analysis. MDR1 gene amplification was not observed in any of the patients tested, including 5 patients in whom ADM was not clinically effective. On the other hand, chemosensitivity tests performed on the tumor cells of these 5 patients indicated resistance to ADM. Our results therefore indicate that MDR1 gene amplification is rarely seen among clinical samples and that conventional chemosensitivity tests might be more useful for the prediction of ADM resistance in cancer patients than the analysis of MDR1 gene amplification.

•The immune factors that determine the pathological and therapeutic effects of preoperative chemotherapy in patients with breast cancer are associated with local and systemic immune responses in the presence of tumor-infiltrating lymphocytes, in collaboration with downregulation of immunosuppressive factors mediated by vascular endothelial growth factor (VEGF) and cytotoxic T lymphocyte antigen 4 (CTLA-4) in regulatory T cells (Tregs) in the tumor microenvironment.•Multivariate analysis showed that grade 2 and better therapeutic effects tended to be associated with higher natural killer cell levels after preoperative chemotherapy (odds ratio = 1.02; 95% confidence interval, 0.99–1.05; p = 0.07).•Therapy targeting VEGF and CTLA-4 in Tregs to overcome tumor-derived immunosuppression may enhance the pathological and therapeutic responses to preoperative chemotherapy in patients with breast cancer.

Abstract: The cellular levels of topoisomerase II expression were compared between 10 fresh human tumors and normal tissues to predict the selective anticancer effect of its inhibitors such as adriamycin and VP-16. Topoisomerase II expression was observed in 9 of the 10 tumor tissues (90.0 per cent), 3 of which showed extremely high levels, whereas only 5 of the normal tissues (50.0 per cent) expressed any cellular topoisomerase II and the levels were not higher than those seen in the cancer cells. Six of the 9 positive tumors showed a higher level of topoisomerase II expression than the normal tissues, while the other 3 showed the same level. It can be interpreted from these results that topoisomerase II inhibitors could be effective in cancer patients due to the greater level of this enzyme in tumor cells than in normal tissues. Thus, it is suggested that a comparative analysis of topoisomerase II expression between tumors and normal tissues may be useful for predicting the selective cytotoxicity of topoisomerase II inhibitors in clinical practice.