benzofurans and Colonic-Neoplasms

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Continuity of Patient Care; Humans; Rectal Neoplasms; Vascular Endothelial Growth Factor A

Here we present a case of metastatic small bowel adenocarcinoma, which progressed after sequential treatment with XELOX (capecitabine and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), cetuximab, HER-2 targeted therapy and apatinib and was then effectively controlled by fruquintinib. Genetic testing showed wild-type KRAS/NRAS/BRAF, HER-2 amplification, and microsatellite stable. Then the patient started to receive fruquintinib and has already achieved a 6-month progression-free survival. Till Jun 2019, the treatment with fruquintinib is still ongoing and no severe adverse effect has been seen so far.. Although fruquintinib is not, at present, a standard therapeutic strategy recommended by the treatment guideline for advanced small bowel adenocarcinoma, the significant curative effect has been seen in our clinical practice.

Topics: Adenocarcinoma; Benzofurans; Colonic Neoplasms; Humans; Intestine, Small; Male; Middle Aged; Palliative Care; Quinazolines

BACKGROUND This study aimed to conduct a systematic review of the literature to identify key randomized controlled clinical trials (RCTs), followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal carcinoma (mCRC). MATERIAL AND METHODS Systematic literature review was performed using the Medline, Embase, and Cochrane library online databases to identify published randomized controlled trials (RCTs). Hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and the odds ratios (ORs) for the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), serious adverse events (SAEs), and fatal adverse events (FAEs) were compared indirectly using network meta-analysis based on a random-effects model. RESULTS Five RCTs that included 2,604 patients fulfilled the eligibility criteria and were analyzed. Indirect comparisons showed that fruquintinib was associated with significant superiority for PFS (HR, 0.57; 95% CI, 0.34-0.95) and DCR (OR, 1.80; 95% CI, 1.08-3.01) when compared with TAS-102 in patients with mCRC. However, there was no significant difference between OS or ORR between regorafenib, fruquintinib, and TAS-102. Fruquintinib was associated with a significantly higher risk of SAEs when compared with TAS-102 or regorafenib. There was no significant difference in the risk of AEs or FAEs following indirect comparison between fruquintinib, regorafenib, and TAS-102. CONCLUSIONS The findings from network meta-analysis showed that fruquintinib was associated with significant superiority for PFS and DCR compared with TAS-102, but fruquintinib was associated with significantly increased risk for SAEs compared with regorafenib and TAS-102.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Pyrrolidines; Quinazolines; Rectal Neoplasms; Thymine; Trifluridine; Uracil

Diarylsulfonylureas represent a class of antitumor agent with significant therapeutic efficacy against rodent and human models of cancer. Despite the exciting preclinical activity of sulofenur, the prototypic agent, clinical activity was poor. Here we review the activity of sulofenur and a second generation diarylsulfonylurea, LY295501 N-[5-(2, 3-dihydrobenzofuryl) sulfonyl]-N'-(3,4-dichlorophenyl)urea, against colon tumor xenografts, and some of the cellular pharmacology of this class of antitumor agents.

Topics: Adenocarcinoma; Adult; Animals; Antineoplastic Agents; Benzofurans; Child; Clinical Trials, Phase I as Topic; Colonic Neoplasms; Drug Resistance, Multiple; Humans; Phenylurea Compounds; Sulfonylurea Compounds; Transplantation, Heterologous

Fruquintinib (anti-vascular endothelial growth factor 1/2/3) plus sintilimab (anti-programmed death-1) demonstrated enhanced anti-tumour effects versus monotherapy in a preclinical study. We investigated the combination in patients with advanced solid tumours, including metastatic colorectal cancer (mCRC).. In this phase 1b/2, open-label, multi-centre, multi-cohort dose-escalation and dose-expansion study, patients with advanced solid tumours (dose-escalation) or mCRC (one cohort in dose-expansion) received different doses of fruquintinib plus a fixed dose of sintilimab once every 4 weeks (Q4W) or 3 weeks (Q3W). Primary objectives were safety, tolerability, and the preliminary efficacy. This study is registered at ClinicalTrials.gov, NCT03903705.. By the data cut-off date (30th December 2021), 23 patients were enrolled in the dose-escalation and 37 patients in the mCRC cohort of the dose-expansion; 44 patients with mCRC who received sintilimab Q3W were pooled for analysis. One dose-limiting toxicity event (grade 3 troponin T increased) occurred during the dose escalation. Grade ≥3 treatment-related adverse events occurred in 43.5% and 47.7% of patients in the dose-escalation phase and pooled mCRC analysis, respectively. Among patients treated with the recommended phase 2 dose (fruquintinib 5 mg once daily, 2 weeks on/1 week off, plus sintilimab 200 mg Q3W) in pooled mCRC analysis, the objective response rate was 23.8% (95% CI 8.2-47.2), median progression-free survival was 6.9 months (95% CI 5.4-8.3), and overall survival was 14.8 months (95% CI 8.8-not reached); in patients with mismatch repair-proficient mCRC, these were 20.0% (95% CI 4.3-48.1), 6.9 months (95% CI 4.8-10.1), and 20.0 months (95% CI 8.1-not reached), respectively.. Fruquintinib plus sintilimab was well tolerated in patients with advanced solid tumours and showed promising efficacy in mCRC.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colonic Neoplasms; Humans; Rectal Neoplasms

Fruquintinib, also called HMPL-013, was first discovered by Hutchison Whampoa Pharmaceuticals Co. Ltd., Shanghai, China, and it is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor. In clinical trials, fruquintinib has demonstrated a survival benefit in metastatic colorectal cancer (mCRC) patients. The purpose of this study was to retrospectively evaluate the efficacy and toxicity of fruquintinib in real-world patients. We collected data from patients with mCRC treated with oral fruquintinib from 2018 to 2020 in six different institutions. Patients with mCRC initially received 5 mg of oral fruquintinib daily for 3 weeks. Progression-free survival (PFS) was evaluated using the KaplanMeier method. The efficacy and safety of fruquintinib were also assessed. Seventy-five patients were involved in our study, and 29.3% of patients achieved stable disease (SD). Median PFS was 5.4 months (95% CI: 4.8415.959). The treatment-emergent adverse events (TEAEs) with fruquintinib were acceptable with grade 3 TEAEs of 6%. The grade 3 TEAEs were handfoot skin reaction (HFSR), fatigue, and stomatitis. The ECOG performance status was associated with PFS. In this real-world study, the clinical activity of fruquintinib was consistent with what has been reported in previous clinical trials. The level of safety was acceptable, and the side effects were manageable.

Topics: Benzofurans; China; Colonic Neoplasms; Colorectal Neoplasms; Humans; Quinazolines; Retrospective Studies; Vascular Endothelial Growth Factor A

Regorafenib and fruquintinib are tyrosine kinase inhibitors that are recommended for refractory colorectal cancer (CRC) in China. However, to date, no head-to-head trials have been conducted to guide clinical practice.. An ambispective observational cohort study was conducted in Beijing Cancer Hospital. Patients with metastatic CRC who received regorafenib or fruquintinib were retrospectively collected between January 2018 and April 2020, and prospectively enrolled between May 2020 and February 2021. The primary outcome was time-to-treatment failure (TTF), and secondary outcomes were overall survival (OS) and adverse events. An additional goal of the study was to explore the appropriate sequence of regorafenib and fruquintinib treatment.. A total of 366 patients with metastatic CRC were enrolled to receive regorafenib (n = 260) or fruquintinib (n = 106) between January 2018 and February 2021. No difference was observed for median TTF (regorafenib 2.7 months vs. fruquintinib 3.1 months, P = .200) or median OS (regorafenib 13.8 months vs. fruquintinib 11.3 months, P = .527). The propensity score analysis showed similar results for median TTF and median OS between the 2 groups, as did the results of subgroup analysis for prospective set (n = 146). For sequence analysis, patients with regorafenib followed by fruquintinib (n = 84) showed longer OS than that with the reverse (n = 29) (28.1 months vs. 18.4 months, P = .024). Most patients tolerated regorafenib at a reduced dose (93.1%), and most patients tolerated fruquintinib at a standard dose (68.9%). The incidences of most adverse events were similar between the two groups, while any grade of hand-foot skin reaction and hyperbilirubinemia were more frequently observed in the regorafenib group and ≥grade 3 hypertension was more common in the fruquintinib group.. Regorafenib and fruquintinib had similar efficacy and toxicity profiles with various frequency. Regorafenib followed by fruquintinib showed longer OS than the reverse, but the sequence needs to be further confirmed.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Humans; Phenylurea Compounds; Prospective Studies; Pyridines; Quinazolines; Rectal Neoplasms; Retrospective Studies

Topics: Apoptosis; Benzofurans; Caspase 3; Cell Line, Tumor; Colonic Neoplasms; Coumarins; Humans; Oxidative Stress; Psoralea; Reactive Oxygen Species

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Development; Drug Screening Assays, Antitumor; Humans; Isatin; Molecular Structure; Proto-Oncogene Proteins c-bcl-2

Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated.. We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis.. We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches.. Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model.. KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers.. KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.

Topics: Activating Transcription Factor 3; Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Colonic Neoplasms; Endoplasmic Reticulum Stress; Gene Expression Profiling; Humans; Mice; Potassium; Stomach Neoplasms

Topics: Animals; Anticarcinogenic Agents; Benzofurans; CHO Cells; Colonic Neoplasms; Cricetinae; Cricetulus; Genomic Instability; Mutagenicity Tests; Precancerous Conditions

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle Checkpoints; Cell Proliferation; Cell Survival; Colonic Neoplasms; Depsides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HeLa Cells; Humans; Hydroxybenzoates; Lactones; Lichens; Molecular Structure; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Salicylates; Uterine Cervical Neoplasms

Salvianolic acid B (SalB) is a water‑soluble phenolic compound, extractable from Salvia miltiorrhiza, and has previously been demonstrated to reverse tumor multidrug resistance (MDR) in colon cancer cells. Cancer stem cells (CSCs) are closely associated with drug resistance. Therefore, establishing a nude mouse model bearing human colon CSCs is important for the study of the mechanisms underlying colon cancer drug resistance as well as the reversal of drug resistance. The present study aimed to establish a nude mouse model bearing human colon CSCs and to investigate the effects of SalB on the drug resistance exhibited by the nude mouse model as well as determine its underlying mechanism. Cells from two colon cancer cell lines (LoVo and HCT‑116) were cultured in serum‑free medium to obtain CSCs‑enriched spheroid cells. Following this, nude mice were transplanted with LoVo and HCT‑116 colon CSCs to establish the CSC nude mouse model, which was subsequently demonstrated to exhibit MDR. The results of the present study revealed that following treatment with SalB, the chemotherapeutic drug resistance of xenografts was reversed to a certain extent. Western blot analysis was performed to investigate the expression levels of cluster of differentiation (CD)44, CD133, transcription factor sox‑2 (SOX2) and ATP‑binding cassette sub‑family G member 2 (ABCG2) proteins, and the results demonstrated that treatment with SalB downregulated the expression of CD44, SOX2 and ABCG2 proteins in both LoVo and HCT‑116 colon CSCs xenografts. In conclusion, the results of the present study revealed that a serum‑free suspension method can be performed to successfully isolate colon CSCs. In addition, a nude mice bearing colon CSCs animal model was successfully established, and associated tumors were confirmed to exhibit MDR. Furthermore, SalB was demonstrated to successfully reverse MDR in nude mice bearing LoVo and HCT‑116 colon CSCs, as well as suppress the expression of CD44, SOX2 and ABCG2 proteins.

Topics: Animals; Benzofurans; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Xenograft Model Antitumor Assays

Colon cancer is one of the most lethal and common malignancies worldwide. STK899704, a novel synthetic agent, has been reported to exhibit anticancer effects towards numerous cancer cells. However, the effect of STK899704 on the biological properties of colon cancer, including cancer cell migration and cancer stem cells (CSCs), remains unknown. Here, we examined the inhibitory effect of STK899704 on cell migration and CSC stemness. In the wound healing assay, STK899704 significantly inhibited the motility of colon cancer cells. Furthermore, STK899704 downregulated the mRNA expression levels of the cell migration mediator focal adhesion kinase (FAK). STK899704 also suppressed mitogen-activated protein kinase kinase and extracellular signal-regulated kinase, which are downstream signaling molecules of FAK. Additionally, STK899704 inhibited stemness gene expression and sphere formation in colon cancer stem cells. These results suggest that STK899704 can be used to treat human colon cancer. [BMB Reports 2018; 51(11): 596-601].

Topics: Benzofurans; Cell Death; Cell Movement; Cell Proliferation; Colonic Neoplasms; Focal Adhesion Protein-Tyrosine Kinases; HT29 Cells; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Neoplastic Stem Cells; Phosphorylation; Signal Transduction

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Levistolide A (LA), a natural compound isolated from the traditional Chinese herb Ligusticum chuanxiong Hort, is used for treating cancer. In this study, we investigated the anticancer effect of LA in HCT116 and its isogenic p53-/- colon cancer cells, as well as the underlying mechanisms.. MTT assay was used to evaluate the effect of LA on the viability of cancer cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined by flow cytometry. Protein expression was detected by western blotting.. The results showed that LA inhibited viability and caused apoptosis of both wild-type and p53-/- HCT116 cells. LA was able to trigger production of ROS and endoplasmic reticulum (ER) stress. Inhibition of ROS using N-acetylcysteine abrogated LA-induced ER stress and apoptosis, as well as the reduction in cancer cell viability.. Our results indicate that LA causes apoptosis of colon cancer cells via ROS-mediated ER stress pathway. It will be interesting to develop the natural compound for chemotherapy of cancers such as CRC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Colon; Colonic Neoplasms; Endoplasmic Reticulum Stress; HCT116 Cells; Humans; Reactive Oxygen Species

Sanggenon C is a well-known, major active agent of the flavonoid derivative of benzopyrone with valuable biological properties, including anticancer, anti-inflammatory, antimicrobial, antiviral, antithrombotic, and immune-modulatory activities. In this study, we investigated the molecular mechanisms by which sanggenon C mediated the induction of cell death in colorectal cancer cells (CRC). Treatment of colorectal cancer cells (LoVo, HT-29 and SW480) with sanggenon C (0, 5, 10, 20, 40 and 80 µM) resulted in inhibited proliferation of colon cancer cells. In addition, Sanggenon C (10, 20, 40 µM) induces apoptosis of HT-29 colon cancer cells as well as the increased ROS generation. Furthermore, treatment with sanggenon C increased the level of intracellular Ca2+ and ATP, while inhibited the nitric oxide production via inhibiting inducible nitric oxide synthase expression. This resulted in the activation of mitochondrial apoptosis pathway as evidenced by the decrease in Bcl-2 protein expression. Consistently, the anti-growth and pro-apoptosis effects of sanggenon C on xenograft colon tumor were further confirmed in vivo. Collectively, our results demonstrated sanggenon C induced apoptosis of colon cancer cells by increased reactive oxygen species generation and decreased nitric oxide production, which is associated with inhibition of inducible nitric oxide synthase expression and activation of mitochondrial apoptosis pathway.

Topics: Animals; Apoptosis; Benzofurans; Chromones; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Mice; Mitochondria; Nitric Oxide; Nitric Oxide Synthase Type II; Reactive Oxygen Species; Xenograft Model Antitumor Assays

MSH3 is a DNA mismatch repair (MMR) gene that undergoes frequent somatic mutation in colorectal cancers (CRCs) with MMR deficiency. MSH3, together with MSH2, forms the MutSβ heteroduplex that interacts with interstrand cross-links induced by drugs such as cisplatin. To date, the impact of MSH3 on chemosensitivity is unknown.. We utilized isogenic HCT116 (MLH1-/MSH3-) cells where MLH1 is restored by transfer of chromosome 3 (HCT116+ch3) and also MSH3 by chromosome 5 (HCT116+3+5). We generated HCT116+3+5, SW480 (MLH1+/MSH3+) and SW48 (MLH1-/MSH3+) cells with shRNA knockdown of MSH3. Cells were treated with 5-fluorouracil (5-FU), SN-38, oxaliplatin, or the histone deacetylase (HDAC) inhibitor PCI-24781 and cell viability, clonogenic survival, DNA damage and apoptosis were analyzed.. MSH3-deficient vs proficient CRC cells showed increased sensitivity to the irinotecan metabolite SN-38 and to oxaliplatin, but not 5-FU, as shown in assays for apoptosis and clonogenic survival. In contrast, suppression of MLH1 attenuated the cytotoxic effect of 5-FU, but did not alter sensitivity to SN-38 or oxaliplatin. The impact of MSH3 knockdown on chemosensitivity to SN-38 and oxaliplatin was maintained independent of MLH1 status. In MSH3-deficient vs proficient cells, SN-38 and oxaliplatin induced higher levels of phosphorylated histone H2AX and Chk2, and similar results were found in MLH1-proficient SW480 cells. MSH3-deficient vs proficient cells showed increased 53BP1 nuclear foci after irradiation, suggesting that MSH3 can regulate DNA double strand break (DSB) repair. We then utilized PCI-24781 that interferes with homologous recombination (HR) indicated by a reduction in Rad51 expression. The addition of PCI-24781 to oxaliplatin enhanced cytotoxicity to a greater extent compared to either drug alone.. MSH3 status can regulate the DNA damage response and extent of apoptosis induced by chemotherapy. The ability of MSH3 to regulate chemosensitivity was independent of MLH1 status. PCI-24781-mediated impairment of HR enhanced oxaliplatin sensitivity, suggesting that reduced DSB repair capacity may be contributory.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Benzofurans; Camptothecin; Cell Death; Cell Nucleus; Cell Survival; Colonic Neoplasms; DNA Damage; DNA Mismatch Repair; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Fluorescent Antibody Technique; Fluorouracil; Gene Knockdown Techniques; HCT116 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Irinotecan; MutL Protein Homolog 1; MutS Homolog 3 Protein; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Rad51 Recombinase

Colorectal cancer (CRC) is the second most frequent cancer in men and the third most common cancer in women in Korea. In spite of the significant advances in conventional therapeutic approaches to CRC, most patients ultimately die of their disease. There is a need to develop novel preventive approaches for this malignancy. This study was carried out to investigate the anticancer effect of the diastereoisomeric compounds, MHY-449 and MHY-450, novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives, on HCT116 human colon cancer cells. MHY-449 exhibited more potent cytotoxicity than MHY-450, against HCT116 cells. Treatment of cells with MHY-449 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner, and inhibition of proliferation in a time-dependent manner. The induction of apoptosis was observed by decreased cell viability, DNA fragmentation, activation of protein levels involved in death receptors. Moreover, activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase and alteration in the ratio of Bax/Bcl-2 protein expression was observed. MHY-449 induced G2/M phase arrest in the cell cycle progression which was observed by flow cytometry analysis, and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25c and Cdc2. MHY-449 also caused increase in the expression levels of p53, a tumor suppressor gene, and p21WAF1/CIP and p27KIP, G2/M phase inhibitors. These results suggest that MHY-449 may be a useful candidate for chemo-prevention and/or treatment of colon cancer.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Benzofurans; Caspases; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Drug; Enzyme Activation; HCT116 Cells; Humans; Naphthyridines; Signal Transduction

Benzonaphthofurandione has been considered as an important class of naturally occurring and synthetic compounds having a variety of biological functions. In this study, we evaluated the antitumor effects of 3-[2-(dimethylamino)isopropoxy]-1-hydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione (8e), a novel benzonaphthofurandione derivative, on the growth of colorectal cancer HCT 116 cells both in vitro culture and an in vivo animal model. Compound 8e exhibited the potential growth inhibition of the colon cancer cells in a concentration-dependent manner. The anti-proliferative activity of 8e was also associated with the induction of cell cycle arrest in the G(0)/G(1) phase. The 8e-induced cell cycle arrest was well correlated with the suppression of cyclin-dependent kinase 2 (CDK2), CDK4, cyclin D1, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb). The tumor growth in xenograft nude mice bearing HCT 116 cells by compound 8e (10mg/kg) also significantly inhibited without any overt toxicity. In addition, the down-regulation of epidermal growth factor receptor (EGFR), Akt, and mTOR signalings were associated with the anti-proliferative activity of compound 8e in colon cancer cells. Taken together, these findings suggested that cell cycle arrest and modulation of cell signal transduction pathways might be the plausible mechanisms of actions for the anti-proliferative activity of 8e, and thus 8e might be used as an effective chemotherapeutic agent in human colon cancer.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Colonic Neoplasms; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Down-Regulation; ErbB Receptors; G1 Phase; Humans; Mice; Mice, Nude; Naphthoquinones; Proto-Oncogene Proteins c-myc; Resting Phase, Cell Cycle; Retinoblastoma Protein; Signal Transduction; TOR Serine-Threonine Kinases; Transplantation, Heterologous

The ethanol extract from the dried exudate of Bursera fagaroides (Burseraceae) showed significant cytotoxic activity in the HT-29 (human colon adenocarcinoma) test system. The extract provided four podophyllotoxin related lignans, identified as (7'R,8R,8'R)-(-)-deoxypodophyllotoxin (3), (7'R,8R,8'R)-(-)-morelensin (4), (8R,8'R)-(-)-yatein (5), and (8R,8'R)-(-)-5'-desmethoxyyatein (6), whose spectroscopic and chiroptical properties were compared with those of (7R,7'R,8R,8'R)-(-)-podophyllotoxin (1) and its acetyl derivative (2). Their absolute configurations were assigned by comparison of the vibrational circular dichroism spectra of 1 and 3 with those obtained by density functional theory calculations.

Topics: 4-Butyrolactone; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Benzofurans; Bursera; Cell Line, Tumor; Circular Dichroism; Colonic Neoplasms; Dioxoles; Drugs, Chinese Herbal; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Phytotherapy; Plant Extracts; Plant Exudates; Podophyllotoxin

This study compared the effects of three anti-mutagenic lichen extracts on colorectal oncogenesis in azoxymethane (AOM)-treated mice and determined whether the extracts also regulated the homeostatic response to genotoxic damage. C57BL/6J mice (n = 12 per group) were treated with the lichen extracts Antimutagen-He (AMH): AMH-C, AMH-D, or AMH-E dimethyl sulfoxide (DMSO, control) for 2 weeks. At the end of the treatment, mice were given a single AOM injection to induce DNA damage and killed 6 h later for measuring apoptosis and proliferation. Apoptotic and proliferation indexes in mice treated with AMH-C, AMH-D, and AMH-E were 0.61%, 1.41%, and 0.77%; and 30.62%, 21.93%, and 27.27%, respectively, which were significantly lower than those of control mice (5.88% and 38.69%) (p < 0.05). To examine the effects of lichen extracts on colorectal cancer, separate groups of mice (n = 25 per group) treated with AMH-C, AMH-D, AMH-E, or DMSO were given 4-weekly AOM injections to induce oncogenesis. Mice were killed 24 weeks after the last AOM injection for assessing colon tumor formation. Colonic tumor incidences were 47.3%, 13%, and 20%; the tumor volumes were 18.47, 2.75, and 10.78 mm(3), respectively, in mice treated with AMH-C (p < 0.05), AMH-D (p < 0.05), and AMH-E (p > 0.05), compared to 24% and 13.28 mm(3) in mice of control correspondingly. No lichen extract showed evident toxic effects on mice. No usnic acid was found in these lichen extracts. The regulation of acute apoptosis and cell proliferation in colonic epithelial cells and the anti-mutagenesis do not seem directly related to the cancer protective effect.

Topics: Adenocarcinoma; Animals; Antimutagenic Agents; Apoptosis; Azo Compounds; Benzofurans; Body Weight; Carcinogens; Cell Proliferation; Colon; Colonic Neoplasms; DNA Damage; Intestinal Mucosa; Lichens; Longevity; Male; Mice; Mice, Inbred C57BL; Plant Extracts

Sparassis crispa (SC), known as Hanabiratake in Japanese, is an edible mushroom with various medicinal properties. We isolated 3 novel phthalides, designated hanabiratakelide A (1), B (2), and C (3), from the SC fruit body. In this investigation, 3 known phthalides (4-6), ubiquinone-9, and 2 known unsaturated fatty acids were also isolated. Their structures were elucidated primarily through extensive NMR experiments. The isolated compounds 1-6 were tested for their anti-oxidant activity. The in vitro superoxide dismutase-like activity of the 3 hanabiratakelides was stronger than that of vitamin C. The compounds also exerted inhibitory effects on lipopolysaccharide-stimulated nitric oxide and prostaglandin E2 production by a murine macrophage cell line, RAW264. In addition, the growth of the colon cancer cell lines Caco-2 and colon-26 was significantly inhibited by treatment with the 3 hanabiratakelides. In vivo, the frequency of azoxymethane-induced aberrant crypt foci was reduced in SC-fed F344/N rats compared to rats fed a standard diet. In conclusion, 3 novel phthalides, hanabiratakelides, derived from SC were shown to possess anti-oxidant, anti-inflammatory, and anti-tumor activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Azoxymethane; Benzofurans; Caco-2 Cells; Cell Proliferation; Colonic Neoplasms; Dinoprostone; Dose-Response Relationship, Drug; Female; Humans; Macrophages; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Nitric Oxide; Polyporales; Rats; Rats, Inbred F344; Superoxide Dismutase

Epidemiological studies suggested that trans-resveratrol, a wine grape component, could prevent malignant tumor development. This compound also demonstrated cytostatic and cytotoxic effects on tumor cells in vitro. To obtain trans-resveratrol derivatives with a better cellular uptake and enhanced antiproliferative effects, we synthesized a triacetate derivative as well as an oligomer, epsilon-viniferin and its acetylated form, epsilon-viniferin penta-acetate. We also obtained vineatrol, a wine grape shoot extract that associates several polyphenols that may act synergistically, including trans-resveratrol and epsilon-viniferin. We show here that resveratrol triacetate and vineatrol are as efficient as trans-resveratrol in inducing the accumulation of human colon cancer cells in early S phase of the cell cycle. This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclin-dependent kinase 2 complex whose kinase activity is increased. In contrast, epsilon-viniferin and its acetylated form do not demonstrate any significant activity on these cells when tested alone. Interestingly, resveratrol triacetate and vineatrol dramatically enhance 5-Fluoro-Uracil-mediated inhibition of colon cancer cell proliferation. Thus, acetylated derivatives of resveratrol have retained the cytostatic and cytotoxic activities of the parental molecule and thus deserve to be tested as chemosensitizers in animal models.

Topics: Antimetabolites, Antineoplastic; Benzofurans; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Colonic Neoplasms; Drug Synergism; Flow Cytometry; Fluorescent Antibody Technique; Fluorouracil; Humans; Immunoenzyme Techniques; Immunoprecipitation; Phenols; Resveratrol; Stilbenes; Tumor Cells, Cultured

To examine the drug efficacy of a novel farnesyltransferase inhibitor (FTI), CH4512600, in vivo, we developed a reliable liver metastasis model of human colon cancer using NOD/Shi-scid IL2Rgamma(null) (NOG) mice. Eleven human colon cancer cell lines were examined for their ability to form diverse metastatic foci in the livers of NOG mice. When inoculated with 10(4) COLO320DM, HCT 116, HT-29, WiDr, LoVo and LS174T cells, liver metastasis was evident in 100% (6/6), 100% (6/6), 88.9% (8/9), 87.5% (7/8), 83.3% (5/6) and 50.0% (3/6) of the NOG mice, respectively. CaCo2, COLO201, LS123, SW48 and SW1417 showed no metastasis when seeded at 10(4) cells even in NOG mice. The mRNA expression levels and genetic mutations of N, H and K-RAS genes, which directly affect the levels of cellular RAS protein that would be molecular target for FTI, were also examined in these six metastatic human colon cancer cell lines for molecular biological and genotypic characteristics. Only three cell lines had a point mutation in the RAS oncogene. LS174T cell line had a point mutation of the K-RAS gene at codon 12 (gly12 --> asp; G12D), and HCT 116 and LoVo cell lines had a point mutation of the K-RAS gene at codon 13 (gly13 --> asp; G13D). Relative gene expression levels of N, H and K-RAS genes in the HCT 116 cell line were 2.6-5.0-fold lower than that of LS174T and LoVo cell lines. We selected HCT 116 cell line from our liver metastasis model for evaluation of FTI CH4512600 efficacy in vivo. Using the NOG mouse liver metastasis model, we demonstrated the effectiveness of FTI CH4512600 to suppress tumor growth in vivo and to prolong mouse survival significantly from 36.9+/-2.9 to 50.3+/-9.4 days.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Colonic Neoplasms; Farnesyltranstransferase; Humans; Imidazoles; Liver Neoplasms, Experimental; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Receptors, Interleukin-2; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

The pleiotrophic cellular response to DNA damage includes activation of cell cycle checkpoints, induction of DNA repair pathways, and initiation of programmed cell death among others. The fate of cells with damaged DNA depends on the coordination of these different responses. The clinical efficacy of genotoxic therapies is influenced by cell fate and thus by how the DNA damage response is coordinated. While a great deal has been learned about how different DNA lesions activate distinct cell cycle checkpoints and DNA repair pathways, less is known about whether the type of DNA lesion influences the qualitative and quantitative nature of the cell death response. To address this question, HCT116 colon carcinoma cells have been treated with equally cytotoxic doses of the antitumor DNA alkylating agents adozelesin or bizelesin or the DNA strand scission agent C-1027. The relative contribution of cell cycle arrest and cell death to measured cytotoxicity varied among the three drugs. Apoptotic cell death accounts for most C-1027 cytotoxicity while cell cycle arrest and cell death both contribute to the cytotoxicity of the alkylating agents. Each of the drugs induces a distinct but overlapping pattern of caspase activation. In addition, the cell death response to these drugs is differentially dependent on p53 and p21. These observations suggest that the type of DNA lesion influences not only the relative extent of apoptotic cell death at a given cytotoxic dose but also the qualitative nature of that response.

Topics: Aminoglycosides; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Benzofurans; Cell Cycle; Cell Death; Cell Proliferation; Colonic Neoplasms; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA Damage; Dose-Response Relationship, Drug; Duocarmycins; Enediynes; HCT116 Cells; Humans; Indoles; Inhibitory Concentration 50; Urea

As members of the cyclopropylpyrroloindole family, adozelesin and bizelesin cause genomic DNA lesions by alkylating DNA. Adozelesin induces single-strand DNA lesions, whereas bizelesin induces both single-strand lesions and double-strand DNA cross-links. At equivalent cytotoxic concentrations, these agents caused different biological responses. Low adozelesin concentrations (e.g., 0.5 nM) induced a transient S-phase block and cell cycle arrest in G(2)-M, as well as increased induction of p53 and p21, whereas a high drug concentration (e.g., 2.5 nM) caused apoptosis but no p21 induction. In contrast, both low and high bizelesin concentrations enhanced p53 and p21 induction and triggered G(2)-M cell cycle arrest and eventual senescence without significant apoptotic cell death. However, in cells lacking p21, bizelesin, as well as adozelesin, triggered apoptosis, indicating that p21 was crucial to sustained bizelesin-induced G(2)-M arrest. Thus, despite similar abilities to alkylate DNA, the chemotherapeutic agents adozelesin and bizelesin caused a decrease in HCT116 tumor cell proliferation by different pathways (i.e., adozelesin induced apoptosis, and bizelesin induced senescence).

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Benzofurans; Cell Cycle; Cellular Senescence; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; Duocarmycins; Humans; Indoles; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Urea

A unique benzofuran named suillusin was isolated from the methanolic extract of the fruiting body of the mushroom Suillus granulatus. Its structure was assigned on the basis of various spectroscopic analyses as a highly substituted novel 1H-cyclopenta[b]benzofuran (1). Suillusin is suggested to be biogenerated from polyporic acid.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Basidiomycota; Benzofurans; Cell Survival; Chromatography, High Pressure Liquid; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; Korea; Lung Neoplasms; Magnetic Resonance Spectroscopy; Male; Melanoma; Molecular Structure; Ovarian Neoplasms; Prostatic Neoplasms; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Tumor Cells, Cultured; Vitamin E

The therapeutic efficacy of the sequence-selective, DNA minor-groove-binding alkylating agent carzelesin was evaluated against a series of human tumor xenografts growing at the s.c. site. The model consisted of seven colon adenocarcinomas, and six pediatric rhabdomyosarcomas. In addition, carzelesin was evaluated against xenografts selected in situ for resistance to vincristine, melphalan, and topotecan. Carzelesin was given as a single i.v. injection, and tumor volumes were determined at 7-day intervals. At the highest dose [0.5 mg/kg, the dose producing 10% lethality (LD10)]), carzelesin significantly inhibited growth in four of six colon tumor lines, causing a high proportion of partial regressions in one of seven lines and complete regressions of VRC5 colon tumors. At 0.25 mg/kg, significant growth inhibition was determined in only two of seven colon tumor lines with infrequent volume regressions. Carzelesin given at the highest nonlethal dose level significantly inhibited the growth of each of six rhabdomyosarcomas, causing a high frequency of partial or complete regressions in four of six tumor lines. There was no apparent cross-resistance to carzelesin in two rhabdomyosarcomas selected for vincristine resistance (Rh12/VCR, Rh18/VCR) or in Rh28/LPAM xenografts selected for primary resistance to the bifunctional alkylating agent melphalan. Interestingly, carzelesin maintained full activity against Rh18/TOPO tumors selected in situ for resistance to topotecan, whereas the colon tumor VRC5/TOPO, selected in a similar manner, was completely resistant to this agent.

Topics: Adenocarcinoma; Adolescent; Adult; Animals; Antineoplastic Agents; Benzofurans; Child; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Duocarmycins; Female; Humans; Indoles; Lethal Dose 50; Male; Mice; Mice, Inbred CBA; Rhabdomyosarcoma; Transplantation, Heterologous; Tumor Cells, Cultured

Antibiotic C3368-A (CA) is produced by a fungus strain from a soil sample collected in Antarctica. CA markedly inhibited radiolabeled thymidine and uridine transport in mouse Ehrlich carcinoma cells, its 50% inhibitory concentration (IC50) being 4.6 and 7.7 microM, respectively. In clonogenic assay, CA displayed a synergistic effect with methotrexate (MTX), mitomycin C (MMC), 5-fluorouracil (5FU), and Adriamycin (ADR) against human oral epidermoid carcinoma KB cells. CA also markedly enhanced the inhibitory effect of 5FU and ADR on the proliferation of human hepatoma BEL-7402 cells as determined by the p-nitrophenyl-N-acetyl-beta-D-glucosaminide (NAG) enzyme-reaction assay. 5FU or ADR cytotoxicity was not augmented by CA in human fetal lung 2BS cells. In vivo, CA significantly potentiated the inhibitory effect of MMC against colon carcinoma 26 in mice. No significant augmentation of toxicity by the combination was found in treated mice. The results suggest that CA, the newly found nucleoside-transport inhibitor, may be useful in potentiation of the effect of antitumor drugs.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Benzofurans; Biological Transport; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Cell Division; Colonic Neoplasms; Doxorubicin; Drug Synergism; Female; Fluorouracil; Humans; KB Cells; Liver Neoplasms; Methotrexate; Mice; Mice, Inbred BALB C; Mitomycin; Spiro Compounds; Thymidine; Tumor Cells, Cultured; Tumor Stem Cell Assay; Uridine

Sulofenur and a second generation diarylsulfonylurea (DSU), N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea (LY295501), were evaluated against a panel of eight colon adenocarcinoma xenografts. Of these tumors, four were derived from adult patients and four from young patients (age range 11-26 years). Both drugs were administered twice daily by oral gavage, 5 days each week for two or three consecutive weeks. The maximum tolerated dose for sulofenur was 300 mg/kg/dose for three courses and 200 mg/kg/dose for LY295501. Against 'adult' derived tumors, sulofenur caused a high proportion of objective regressions of advanced xenografts in two of four lines, with significant inhibition of growth in three tumor lines. Colon adenocarcinomas from young patients were similarly sensitive to sulofenur with a high proportion of complete and partial responses in two of three lines. LY295501 demonstrated a very similar spectrum of activity against this panel of xenografts. Tumors intrinsically resistant to sulofenur were resistant to LY295501, although this agent was slightly more active than sulofenur against tumors from younger patients. In addition, xenografts were established from a cloned colon adenocarcinoma line (GC3/c1) and its derivative GC3/LYC5) selected in vitro for resistance to sulofenur. GC3/c1 xenografts were highly responsive to both sulofenur and LY295501, whereas GC3/LYC5 xenografts were completely resistant to both agents administered at the maximum tolerated dose and schedule. These results indicate that the second generation DSU, LY295501, demonstrates a similar spectrum of activity against colon tumors as does sulofenur, and that the mechanism of action and/or resistance to the two drugs is probably similar.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzofurans; Colonic Neoplasms; Female; Humans; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Phenylurea Compounds; Sulfonylurea Compounds; Transplantation, Heterologous

Adozelesin (Ado), a CC-1065 analog, shows significant antineoplastic activity in vivo against several types of murine tumors and human tumor xenografts. Ado is a DNA alkylating agent. One objective of this study was to investigate the cytotoxic action of Ado against the human colon (HT-29, DLD-1) and the lung (SK) carcinoma cell lines. The concentrations of Ado that produced 50% cell kill for a 4 and 24 h exposure were in the range of 0.001-0.02 ng/ml for both colon and lung carcinoma cells, indicating that this analog was a very potent cytotoxic agent. Since most clinical regimens for tumor therapy consist of several drugs, we investigated the antineoplastic action of Ado in combination with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation or cytosine arabinoside (Ara-C), a potent inhibitor of DNA synthesis. The Ado plus 5-Aza-CdR combination showed a synergistic effect on cytotoxicity of DLD-1 colon carcinoma cells for both a 6 and 24 h exposure. However, combination of Ado and Ara-C for a 6 h exposure showed an antagonistic effect, whereas a 24 h exposure showed a synergistic effect. These preclinical results provide some preliminary data on possible drugs that can be selected for use in combination with Ado in future clinical trials in patients with cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzofurans; Carcinoma, Squamous Cell; Cell Division; Colonic Neoplasms; Cyclohexanecarboxylic Acids; Cyclohexenes; Cytarabine; Decitabine; DNA, Neoplasm; Drug Screening Assays, Antitumor; Duocarmycins; Humans; Indoles; Lung Neoplasms; Time Factors; Tumor Cells, Cultured

The cyclopropylpyrroloindole analogues are DNA minor-groove binders containing a cyclopropyl group, which mediates N3-adenine covalent adduct formation in a sequence-selective fashion. Carzelesin (U-80244) is a cyclopropylpyrroloindole prodrug containing a relatively nonreactive chloromethyl precursor to the cyclopropyl function. Activation of carzelesin requires two steps, (a) hydrolysis of a phenylurethane substituent to form U-76073, followed by (b) ring closure to form the cyclopropyl-containing DNA-reactive U-76074. The formation of the DNA-reactive U-76074, via U-76073, from carzelesin was shown to proceed very slowly in phosphate-buffered saline (t1/2 greater than 24 h) but to occur rapidly in plasma from mouse, rat, dog, and human (initial t1/2 values ranging from 18 min for mouse to 52 min for rat) and in cell culture medium (t1/2 approximately 40 min). Although carzelesin was less potent in terms of in vitro cytotoxicity and in vivo optimal dosage and showed low affinity for binding to DNA, it was therapeutically more efficacious against mouse L1210 leukemia than was U-76074 or adozelesin (U-73975), another cyclopropylpyrroloindole analogue which is currently in phase I clinical trials. Carzelesin also proved to be more efficacious than U-76074 or adozelesin against mouse pancreatic ductal 02 adenocarcinoma, a system reported to be resistant to every agent tested. Carzelesin was highly effective against this tumor and produced 97% tumor growth inhibition. In addition, i.v. administered carzelesin showed significant activity (National Cancer Institute criteria) against i.v. or s.c. implanted Lewis lung carcinoma, i.p. or s.c. implanted B16 melanoma, s.c. implanted colon 38 carcinoma, and five s.c. implanted human tumor xenografts, including clear cell Caki-1 carcinoma, colon CX-1 adenocarcinoma, lung LX-1 tumor, ovarian 2780 carcinoma, and prostatic DU-145 carcinoma. Carzelesin treatment produced 100% complete remissions (no palpable tumor mass at the termination of the experiment) in mice bearing early-stage human ovarian 2780. Pharmacologically, carzelesin proved to be relatively schedule and route independent and was highly active against i.p. implanted L1210 leukemia, regardless of whether the analogue was given i.v., i.p., s.c., or p.o. These results, collectively, suggest that carzelesin is absorbed and distributed well. Both carzelesin and adozelesin caused marked tumor shrinkage in mice bearing human lung LX-1 or advanced-stage human ovar

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzofurans; Cell Survival; Colonic Neoplasms; Culture Media; Duocarmycins; Indoles; Leukemia L1210; Metabolic Clearance Rate; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Plasma; Prodrugs; Transplantation, Heterologous

U-73,975 (U-73) and U-77,779 (U-77), two analogues of the cyclopropylpyrroloindole antitumor antibiotic CC-1065, are promising novel chemotherapeutic agents which are known to alkylate the N3 position of adenine in a sequence-selective manner. The concentration of U-73 required to produce a 1 log cell kill in 6 human tumor cell lines varied from 20-60 pM. U-77 was more cytotoxic than U-73, with the concentrations required for a 1 log cell kill ranging from 1-20 pM. The cytotoxicity of U-73 and U-77 was found to be independent of the guanine O6-alkyltransferase phenotype. The sensitivity of the BE and HT-29 human colon carcinoma cells was increased when the time of drug exposure was increased from 2 to 6 h. DNA interstrand cross-links, as measured by the technique of alkaline elution, could only be detected when HT-29 or BE cells were exposed to extremely high concentrations of U-77 for 6 h. No other forms of DNA damage were detected in genomic DNA with either compound. U-77 was also found to induce DNA interstrand cross-links in naked DNA, as measured by an agarose gel method. The rate of interstrand cross-linking was extremely rapid with the "second-arm" of the cross-link being completed within 2 h. The mechanism by which these cyclopropylpyrroloindole compounds elicit their cytotoxicity, however, remains to be elucidated.

Topics: Antibiotics, Antineoplastic; Benzofurans; Carcinoma; Cell Death; Colonic Neoplasms; Cross-Linking Reagents; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA Damage; Dose-Response Relationship, Drug; Duocarmycins; Humans; Indoles; Leucomycins; Lung Neoplasms; Plasmids; Tumor Cells, Cultured; Urea

Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p. - or s.c.- implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.

Topics: Animals; Antineoplastic Agents; Benzofurans; Colonic Neoplasms; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA, Neoplasm; Duocarmycins; Female; Humans; Indoles; Leukemia L1210; Leukemia, Experimental; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Pancreatic Neoplasms; Sarcoma, Experimental

The mechanisms of the resistance of intestinal cancer to anthracyclines were studied on an experimental model of rat colon cancer cells. The accumulation of anthracyclines in the nucleus of living cancer cells was observed by fluorescence microscopy. This accumulation depended on both the capacity of anthracyclines to penetrate into the cell and the activity of an efflux mechanism extruding the drug from the cell. We found that 4'-deoxydoxorubicin was superior to 4 other anthracyclines in its capacity to penetrate into confluent colon cancer cells. Amiodarone, an antiarrhythmic agent used in cardiology, inhibited the efflux mechanism efficiently and increased the toxicity of anthracyclines to the colon cancer cells. Association of amiodarone and 4'-deoxydoxorubicin was able to cure 5 of 13 rats that had been inoculated i.p. previously with syngeneic colon cancer cells. This association could be of interest in the treatment of human colon cancer.

Topics: Adenocarcinoma; Amiodarone; Animals; Benzofurans; Cell Division; Cell Nucleus; Cells, Cultured; Colonic Neoplasms; Doxorubicin; Drug Synergism; In Vitro Techniques; Microscopy, Fluorescence; Rats