Jong Ho Chun

This study provides evidence to support the concept proposed by Kimura et al. in 2023 that the inhibitors of SP1, MYC, and HIF1A should induce strong anticancer activity by reducing the expression of stem cell-related proteins. In LN229 and U87MG glioblastoma cells, either tetra-methyl-O-nordihydroguaiaretic acid (M₄N) or tetra-acetyl-O-nordihydroguaiaretic acid (A₄N) suppressed SP1 and only a few stem cell-related proteins and induced only a small amount of cell death; in contrast, the combination treatment of M₄N with A₄N greatly suppressed the expression of SP1, MYC, and HIF1A, as well as all of the stem cell-related proteins examined, and greatly induced cell death. The bioinformatic analysis showed that the proteins associated with SP1, MYC, and HIF1A were specifically involved in the regulation of transcription and that various microRNAs (miRNAs) that had been shown to induce either anti- or procancer activity were associated with SP1, MYC, and HIF1A, which suggested that the inhibition of SP1, MYC, and HIF1A could modulate the transcription of both coding and noncoding RNAs and affect cancers. These data overall supported our concept.

Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M₄N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M₄N, the M₄N concentration in most of the organs in mice reached ~1 μM (the M₄N concentration in intestines and fat pads was as high as 20–40 μM) and treatment with the combination of M₄N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M₄N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M₄N suppressed oxygen consumption in cultured LN229 cells, indicating that M₄N inhibited oxidative phosphorylation. Treatment with M₄N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M₄N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M₄N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M₄N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M₄N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M₄N has beneficial effects on normal tissues. The dual ability of combination treatment with M₄N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.

A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m² i.v. on days 1 and 8 plus X 1000 mg/m² p.o. b.i.d. on days 1–14 of a 21-day cycle (level I) or T 30 mg/m² i.v. on days 1 and 8 plus X 625 mg/m² p.o. b.i.d. on days 1–14 of a 21-day cycle (level II). A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m² i.v. on days 1 and 8 plus X 625 mg/m² p.o. b.i.d. on days 1–14 of a 21-day cycle.

BACKGROUND.: Irinotecan (I) and cisplatin (P) are active chemotherapy agents with clinical synergy in non–small‐cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum‐containing regimen(s).METHODS.: Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0‐2, and progressive disease after nonplatinum‐based chemotherapy. Treatment consisted of I (65 mg/m²) and P (30 mg/m²) i.v. on Days 1 and 8 of a 21‐day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients.RESULTS.: Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42–74) were enrolled. Twenty‐four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty‐five patients had adenocarcinoma and 6 had squamous‐cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow‐up of 18.5 months, the median survival time was found to be 9.3 months, with a 1‐year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity.CONCLUSIONS.: The irinotecan and cisplatin combination is an active and well‐tolerated regimen for the patients with advanced NSCLC that progressed after nonplatinum‐containing regimen(s). Cancer 2006. © 2006 American Cancer Society.

The current treatment for metastatic gastric cancer (MGC) consists of cisplatin and/or fluorouracil (5-FU) based combination chemotherapy, but cisplatin-based regimens are associated with considerable toxicity. We evaluated the efficacy and safety of a noncisplatin-, non-5-FU-containing regimen, docetaxel/irinotecan in MGC. Chemo-naive patients with MGC received docetaxel (30 mg m⁻²) and irinotecan (70 mg m⁻²) on days 1 and 8 every 3 weeks. The 48 eligible patients (median age 56 years) received a median of four cycles of docetaxel/irinotecan (range 1–18). Of the 46 patients in whom efficacy could be evaluated, 21 showed a partial response (response rate=45.7%; 95% confidence interval (CI) 31.3–60.1%). At a median follow-up of 15.0 months, the median time to progression was 4.5 months (95% CI 3.8–5.2 months) and overall survival was 8.2 months (95% CI, 5.8–10.6 months). Grade 3/4 neutropenia developed in 57.4% of patients, and febrile neutropenia/neutropenic infection in 19.1%. Nonhaematological toxicities were moderate; grade 3/4 diarrhoea occurred in 19.1% of patients, however, was manageable by a dose reduction. There was one possible treatment-related death. In conclusion, weekly docetaxel/irinotecan is a promising outpatient regimen in MGC, with appropriate dose modification.

Notch signaling is implicated in stem cell self-renewal, differentiation, and other developmental processes, and the Drosophila hairy and enhancer of split (HES) 1 basic helix-loop-helix protein is a major downstream effector in the Notch pathway. We found that HES1 was expressed at high levels in the hematopoietic stem cell (HSC)–enriched CD34+/[CD38/Lin]− /low subpopulation but at low levels in more mature progenitor cell populations. When CD34+ cells were cultured for 1 week, the level of HES1 remained high in the CD34+ subset that had remained quiescent during ex vivo culture but was reduced in CD34+ cells that had divided. To investigate the effects of HES1 in human and mouse hematopoietic stem–progenitor cells (HSPCs), we constructed conditional lentiviral vectors (lentivectors) to introduce transgenes encoding either wild-type HES1 or a mutant lacking the DNA-binding domain (ΔBHES1). We found that lentivector-mediated HES1 expression in CD34+ cells inhibited cell cycling in vitro and cell expansion in vivo, associated with upregulation of the cell cycle inhibitor p21cip1/Waf1 (p21). The HES1 DNA–binding domain was required for these actions. HES1 did not induce programmed cell death or alter differentiation in HSPCs, and while short-term repopulating activity was reduced in HES1-transduced mouse and human cells, long-term reconstituting HSC function was preserved. Our data characterize the complex, cell context–dependent actions of HES1 as a major downstream Notch signaling regulator of HSPC function.

In several recent reports, docetaxel (75–85 mg/m2) combined with fluorouracil (5-FU) and cisplatin has shown considerable efficacy but significant toxicities, especially neutropenia, in patients with advanced gastric cancer. The authors tested the efficacy and safety of a lower dose (50 mg/m2) of docetaxel, combined with 5-FU and cisplatin, in metastatic gastric cancer (MGC). Chemonaive patients with MGC received docetaxel (50 mg/m2 on day 1), cisplatin (80 mg/m2 on day 1), and 5-FU (1200 mg/m2 on days 1–3) every 21 days. Forty-seven patients with a median age of 55 years (range, 30–73 years) received a median of 4 cycles (range, 1–13+ cycles). Of the 42 efficacy-“evaluable” patients, 17 showed a partial response (response rate, 40%; 95% confidence interval [CI], 26–55) according to the independent review panel. With a median follow-up of 12.6 months for all patients, the median time to progression was 4.6 months (95% CI, 3.6–5.6 months) and overall survival was 9.7 months (95% CI, 8.4–11.0 months). Grade 3/4 neutropenia developed in 68% of patients, and febrile neutropenia/neutropenic infection occurred in 26%. The most common grade 3/4 nonhematologic toxicity was stomatitis (21%), followed by syncope (6%), diarrhea (4%), peripheral neuropathy (4%), dizziness (2%), constipation (2%), and abnormal liver function tests (2%). There was 1 possible treatment-related death. Lower dose (50 mg/m2) docetaxel combined with 5-FU and cisplatin was active in MGC with a tolerable toxicity profile.

Docetaxel (T) and capecitabine (X) are active agents against gastric cancer with synergistic antitumor effects. We conducted the current phase II study to assess the response rate and toxicity of combination TX regimen in patients with metastatic gastric cancer. Eligible patients were treated with docetaxel (36 mg/m2 intravenously) on days 1 and 8 and capecitabine (1000 mg/m2 orally twice a day) on days 1–14 of a 3-week schedule until progression occurred. From December 2001 to May 2003, 55 patients with median age of 54 years (range, 22–73 years) were enrolled; 47 patients had measurable lesions. A total of 358 courses of treatment were given, with a median of 5 (range, 1–22+) per patient. Objective responses were documented in 19 of 47 patients with measurable lesions (response rate, 40.4%; 95% confidence interval [CI], 25.9–54.9), with the median response duration of 5.6 months (range, 2.1–13.6+). At a median follow up of 15.9 months for all of 55 study patients, the median time to progression and survival were 4.5 months (95% CI, 3.4–5.6) and 12.0 months (95% CI, 7.5–16.6), respectively. Hematologic toxicities were mild to moderate, and the observed grade 3 nonhematologic toxicities, the most frequent of which was stomatitis, were generally manageable. Four patients experienced pneumonitis, but all of them responded to steroid treatment. The TX regimen was relatively well tolerated and effective against metastatic gastric cancer, with the added advantage of being an outpatient regimen.

To gain insight into clinically relevant mechanisms of irinotecan resistance, we undertook oligonucleotide microarray analyses on paired malignant effusion samples obtained from eight gastric cancer patients treated with weekly irinotecan. Pretreatment and posttreatment (48 h) effusion samples were obtained for each patient, and the change in expression profile was compared between clinical responders and nonresponders. When differences in the expression of genes were examined using SAM (Significance Analysis of Microarrays) software, five isoforms of the metallothionein family were identified to have significantly higher signal log ratios in five nonresponders, compared with three responders. Compared with control cells, metallothionein 1X (MT1X)-transfected AGS cells showed a 1.4-fold higher irinotecan IC50 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and tended to form more colonies. These findings collectively suggest that irinotecan-induced up-regulation of metallothionein might be associated with irinotecan resistance in patients with gastric cancer, although it remains to be confirmed in a larger data set.