-
Cancer Control : Journal of the Moffitt... 2022Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this... (Clinical Trial)
Clinical Trial
OBJECTIVE
Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.
METHODS
The study was a prospective, single-center, non-randomized, open-label phase II clinical trial. Patients with mCRC after failure with oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m) and raltitrexed (2.5 mg/m) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AEs).
RESULTS
Between December 2012 and October 2016, 33 and 35 patients enrolled were assessed for response and safety, respectively. The ORR was 8.6%, and the DCR was 71.4%. The median PFS was 4.5 months (95% CI 3.8-5.2). The median OS was 12.0 months (95% CI 8.5-15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 AEs were anorexia (14.3%), vomiting (14.3%), nausea (11.4%), fatigue (8.6%), and leukopenia (8.6%). No one died from treatment-related events. The incidence and severity of toxicity were irrelevant to UGT1A1 status.
CONCLUSIONS
The combination of irinotecan with raltitrexed is an efficient, convenient, and acceptable toxic regimen for second-line treatment for mCRC patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Irinotecan; Prospective Studies; Quinazolines; Thiophenes
PubMed: 35343258
DOI: 10.1177/10732748221080332 -
Malawi Medical Journal : the Journal of... Sep 2021Metastasis from extramammary primary tumor to breast is extremely rare. (Review)
Review
BACKGROUND
Metastasis from extramammary primary tumor to breast is extremely rare.
CASE SUMMARY
A 59-year-old woman with 1-year history of rectal cancer presented with asymptomatic breast mass. At 16 months after the diagnosis of rectal mucinous adenocarcinoma, a breast mass was confirmed by ultrasonography and identified by pathology and immunohistochemistry as a metastasis from the rectal cancer. Treatments included chemotherapy (6 cycles: 300 mg irinotecan on day 1, 4.5 mg raltitrexed on day 2, 450 mg bevacizumab on day 3), radiotherapy, and surgical resection. Two years of follow-up examinations (6-months intervals) showed no evidence of recurrence or novel distant metastasis.
CONCLUSION
Breast metastasis from rectal carcinoma is a rare secondary malignancy. Final diagnosis can be established by histopathology and immunohistochemistry.
Topics: Breast Neoplasms; Carcinoma; Female; Humans; Melanoma; Middle Aged; Rectal Neoplasms; Skin Neoplasms
PubMed: 35233281
DOI: 10.4314/mmj.v33i3.11 -
FEBS Letters Feb 2022A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and...
A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. γ-Glutamyl hydrolase (GGH) catalyzes the removal of γ-polyglutamate tails of folylpoly-/antifolylpoly-γ-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH ) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH . Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition. Our findings clearly define the in vivo role of GGH in ALL cells and indicate a novel modulation of the GGH function, suggesting new avenues for ALL treatment in future.
Topics: CRISPR-Cas Systems; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Gene Editing; Glycosylation; HeLa Cells; Humans; Lymphocytes; Lysosomes; Methotrexate; Polyglutamic Acid; Protein Sorting Signals; Quinazolines; Thiophenes; gamma-Glutamyl Hydrolase
PubMed: 35040120
DOI: 10.1002/1873-3468.14285 -
American Journal of Translational... 2021To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of...
OBJECTIVE
To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of intermediate and advanced primary hepatocellular carcinoma (PHC).
METHODS
One hundred patients with intermediate or advanced PHC were randomly divided into a control group (the CG, n=50) and an observation group (the OG, n=50). The CG was treated with conventional TACE (cTACE), and the OG was treated with DEB-TACE loaded with epirubicin and raltitrexed. The overall efficiency, the liver function indices, the tumor markers, the macrophage migration inhibitory factor (MIF) levels , the lesion diameters, the Child-Pugh scores, the adverse reactions, the median times to disease progression, the 1-year and 2-year recurrence rates, and the survival rates were compared between the two groups.
RESULTS
At 6 months after the surgery, the overall response rate in the OG (82.00%) was higher than it was in the CG (62.00%) (<0.05). The serum alanine aminotransferase, total bilirubin, and aspartate aminotransferase levels were elevated in both groups after the intervention, but they were lower in the OG than they were in the CG (<0.05). The serum alpha-fetoprotein, carcinoembryonic antigen, and MIF levels, and the lesion diameters were lower in both groups at one month after the intervention, and they were lower in the OG than they were in the CG (<0.05). The incidence of abnormal blood test results in the OG was lower than it was in the CG (<0.05). The OG also exhibited a longer median time to disease progression, lower 1-year and 2-year recurrence rates, and higher 1- and 2-year survival rates than the CG (<0.05).
CONCLUSION
DEB-TACE loaded with epirubicin and raltitrexed improves the short-term outcomes, reduces the tumor load, decreases the incidence of adverse events, and improves the survival rate in patients with intermediate and advanced PHC.
PubMed: 34540079
DOI: No ID Found -
Bioactive Materials Jan 2022Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy. Herein, a pH-responsive gold nanoassembly is designed to overcome these...
Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy. Herein, a pH-responsive gold nanoassembly is designed to overcome these problems. Polyethylene glycol linked raltitrexed (RTX, target ligand and chemotherapy drug) and two tertiary amine molecules (1-(2-aminoethyl) pyrrolidine and -dibutylethylenediamine) are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX). The Au-NNP (RTX) nanoassembly could remain at about 160 nm at the blood circulation (pH 7.4), while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH (pH 6.8). This pH-responsive disassembly behavior endows Au-NNP(RTX) better tumor tissue permeability through the better diffusion brought by the size reduction. Meanwhile, after disassembly, more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability. Most importantly, the results show that Au-NNP(RTX) possesses of high tumor accumulation and effective tumor penetration, thereby enhancing the tumor chemo-radiotherapy efficiency.
PubMed: 34466739
DOI: 10.1016/j.bioactmat.2021.05.050 -
Pharmaceuticals (Basel, Switzerland) Jul 2021To treat colorectal liver metastases, intra-arterial chemotherapies may complete therapeutic arsenal. Drugs using intra-arterially are very heterogeneous. The aim of...
To treat colorectal liver metastases, intra-arterial chemotherapies may complete therapeutic arsenal. Drugs using intra-arterially are very heterogeneous. The aim of this study was to select the most efficient drug on a panel of colorectal cancer (CRC) cell lines (Caco-2, HCT 116, HT 29, SW 48, SW 480, SW 620) exposed for 30 min to 12 cytotoxic agents (doxorubicin, epirubicin, idarubicin, 5-FU, raltitrexed, gemcitabine, cisplatin, oxaliplatin, mitomycin C, irinotecan, streptozocin, paclitaxel) at different concentrations. The effect on cell viability was measured using the WST-1 cell viability assay. For each drug and cell line, the IC and IC were calculated, which respectively correspond to the drug concentration (mg/mL) required to obtain 50% and 90% of cell death. We also quantified the cytotoxic index (CyI = C Max/IC) to compare drug efficacy. The main findings of this study are that idarubicin emerged as the most cytotoxic agent to most of the tested CRC cell lines (Caco-2, HT29, HCT116, SW620 and SW480). Gemcitabine seemed to be the most efficient chemotherapy for SW48. Interestingly, the most commonly used cytotoxic agents in the systemic and intra-arterial treatment of colorectal liver metastasis (CRLM) (oxaliplatin, 5-FU, irinotecan) showed very limited cytotoxicity to all the cell lines.
PubMed: 34358065
DOI: 10.3390/ph14070639 -
Virology Sep 2021Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1...
Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1 showed that many enzymes related to the folate cycle pathway, such as TS, are upregulated in productively infected cells. Here, we suggest that TS is essential for an effective HIV-1 infection in MDMs. Indeed, a TS specific small interfering RNA (siRNA) as well as the TS specific inhibitor Raltitrexed (RTX) caused a reduction in productively infected cells. Quantitative PCR analysis showed that this treatment decreased the efficacy of the early steps of the viral cycle. The RTX inhibitory effect was counteracted by dNTP addition. These results suggest that TS is essential for the early stages of HIV-1 infection by providing optimal dNTP concentrations in MDMs. TS and its related pathway may thus be considered as a potential therapeutic target for HIV-1 treatment.
Topics: Cells, Cultured; Enzyme Inhibitors; HIV-1; Humans; Macrophages; Quinazolines; RNA Interference; RNA, Small Interfering; SAM Domain and HD Domain-Containing Protein 1; Thiophenes; Thymidylate Synthase; Thymine Nucleotides; Virus Replication
PubMed: 34146963
DOI: 10.1016/j.virol.2021.05.002 -
BMC Gastroenterology May 2021The clinical outcomes of drug-eluting beads transarterial chemoembolization (DEB-TACE) with doxorubicin-loaded CalliSpheres® beads for patients with unresectable or...
BACKGROUND
The clinical outcomes of drug-eluting beads transarterial chemoembolization (DEB-TACE) with doxorubicin-loaded CalliSpheres® beads for patients with unresectable or recurrent esophageal carcinoma have not been reported. The aim of this study is to study the clinical outcomes of DEB-TACE for patients with unresectable or recurrent esophageal carcinoma.
METHODS
This retrospective study enrolled 21 patients (15 men; mean age 68.7 ± 9.7; range 46-86 years) with unresectable or recurrent esophageal carcinoma received DEB-TACE between July 2017 and September 2020. Patient characteristic data, imaging findings, complications and DEB-TACE procedure were reviewed. The primary endpoints, disease control rate (DCR) and objective response rate (ORR), were calculated. The secondary endpoints were overall survival rate and progression-free survival (PFS).
RESULTS
Twenty-two sessions of DEB-TACE were performed in 21 patients. The technical success rate was 100%; without sever adverse events or procedure-related deaths. All patients received transarterial chemotherapy infusion with raltitrexed or oxaliplatin. The median follow-up period was 3.6 months (interquartile range, IQR 1.5-9.4 months). ORR and DCR were 42.9 and 85.7%, 28.6 and 71.4%, 20.0 and 40.0% respectively at 1-, 3-, and 6-months after DEB-TACE. The median PFS was 6.0 months, and the 3-, 6- and 12-month PFS rates were 68.2%, 45.5 and 0.0%, respectively. The median overall survival was 9.4 months, and the 3-, 6- and 12-month overall survival rates were 75.5%, 55.0 and 13.8%, respectively.
CONCLUSIONS
To our knowledge, this is the first study reports outcomes of DEB-TACE with doxorubicin-loaded CallSpheres bead treatment in the management of patients with unresectable or recurrent esophageal carcinoma. According to our results, this is a safe and feasible treatment modality that may be considered among the options for the treatment of these patients.
Topics: Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome
PubMed: 34020608
DOI: 10.1186/s12876-021-01816-3 -
World Journal of Surgical Oncology May 2021Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective routine treatments for colorectal peritoneal metastasis (PM). However,...
Neoadjuvant chemotherapy followed by hyperthermic intraperitoneal chemotherapy for patients with colorectal peritoneal metastasis: a retrospective study of its safety and efficacy.
BACKGROUND
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective routine treatments for colorectal peritoneal metastasis (PM). However, the safety and efficacy of neoadjuvant chemotherapy (NAC) before CRS+HIPEC are poorly understood. Therefore, this study aimed to assess the perioperative safety and long-term efficacy of NAC prior to CRS+HIPEC for patients with synchronous colorectal PM.
METHODS
Patients with synchronous colorectal PM who received NAC prior to CRS+HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. The clinicopathologic characteristics, perioperative parameters, and survival rates of patients who underwent CRS+HIPEC with NAC (NAC group) and patients who underwent CRS+HIPEC without NAC (non-NAC group) were compared.
RESULTS
The study enrolled 52 patients, with 20 patients in the NAC group and 32 in the non-NAC group. In the NAC group, the proportion of patients with a peritoneal carcinomatosis index (PCI) score < 12 was significantly higher than that in the non-NAC group (80.0% vs 50.0%, P = 0.031), and more patients achieved complete cytoreduction (80.0% vs 46.9%, P = 0.018). The two groups had comparable grade III/IV complications and similar reoperation and mortality rates (P > 0.05). However, patients who received NAC had lower platelet counts (151.9 vs 197.7 × 10/L, P = 0.036) and neutrophil counts (4.7 vs 7.2 × 10/L, P = 0.030) on postoperative day 1. More patients survived for 2 years in the NAC group than in the non-NAC group (67.4% vs 32.2%, respectively, P = 0.044). However, the completeness of cytoreduction score (HR, 2.99; 95% CI, 1.14-7.84; P = 0.026), rather than NAC, was independently associated with overall survival (OS) in the multivariate analysis after controlling for confounding factors.
CONCLUSION
NAC administration before CRS+HIPEC can be regarded as safe and feasible for patients with colorectal PM with comparably low mortality rates and acceptable morbidity rates. Nevertheless, large-sample randomized controlled studies are needed to confirm whether the administration of NAC before CRS+HIPEC confers a survival benefit to patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; China; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Humans; Hyperthermia, Induced; Hyperthermic Intraperitoneal Chemotherapy; Neoadjuvant Therapy; Peritoneal Neoplasms; Prognosis; Retrospective Studies; Survival Rate
PubMed: 34001125
DOI: 10.1186/s12957-021-02255-w -
Cancers Apr 2021Combining drugs represent an approach to efficiently prevent and overcome drug resistance and to reduce toxicity; yet it is a highly challenging task, particularly if...
Combining drugs represent an approach to efficiently prevent and overcome drug resistance and to reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors of the same enzyme target are considered. To show that crystallographic and inhibition kinetic information can provide indicators of cancer cell growth inhibition by combinations of two anti-human thymidylate synthase (hTS) drugs, we obtained the X-ray crystal structure of the hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex. Its analysis showed a ternary complex with both molecules strongly bound inside the enzyme catalytic cavity. The synergistic inhibition of hTS and its mechanistic rationale were consistent with the structural analysis. When administered in combination to A2780 and A2780/CP ovarian cancer cells, the two drugs inhibited ovarian cancer cell growth additively/synergistically. Together, these results support the idea that X-ray crystallography can provide structural indicators for designing combinations of hTS (or any other target)-directed drugs to accelerate preclinical research for therapeutic application.
PubMed: 33923290
DOI: 10.3390/cancers13092061