Cancer Chemotherapy and Pharmacology最新文献

Purpose: Adherence to 6-mercaptopurine (6-MP)/methotrexate maintenance treatment for acute lymphoblastic leukemia (ALL) is pivotal to preventing relapse, and the 6-MP metabolite DNA-incorporated thioguanine (DNA-TG) is associated with relapse risk. In the ALLTogether-1 (A2G1) Maintenance sub-study (EU CT nr 2022-501050-11-01), DNA-TG, thioguanine nucleotides (TGN), and methylated mercaptopurine metabolites (MeMP) are analyzed regularly. Upon levels below preset limits (TGN < 50, or MeMP < 200 or < 100 nmol/mmol hemoglobin for thiopurine S-methyltransferase (TPMT) wild type and heterozygous patients, respectively), the treating physician is informed of potential non-adherence. We investigated the feasibility of using DNA-TG as the primary flagging of potential non-adherence.

Methods: We analyzed 6-MP metabolites in 3,074 blood samples from 368 children enrolled in the A2G1 Maintenance sub-study.

Results: In 6% of samples, TGN (median 212, 95% range 40-642), MeMP (median 4,959, 95% range 135-23,880) or both were below the flagging potential non-adherence limits. DNA-TG was associated with TGN (estimate = 1.72, p < 0.0001), MeMP (estimate = 1.10, p < 0.0001), and prescribed 6-MP dose (estimate = 1.083 and 1.132, p < 0.0001, for TPMT wild type and heterozygous patients) in linear effects models, and the predicted probability of treatment interruption in logistic regression models. DNA-TG was below 200 fmol TG/µg DNA (13th percentile of all measurements, median 569, 95% range 73-1,823) in all samples with both TGN and MeMP below the flagging potential non-adherence limits.

Conclusion: DNA-TG can provide a cost-effective guidance on when to measure TGN and MeMP to determine whether non-adherence should be suspected, which is an additional benefit to monitoring DNA-TG during maintenance therapy.

Purpose: The impact of the unrecognized mutational dihydropyrimidine-dehydrogenase-gene-(DPYD)-status on high-grade CTC-AE-grades ≥ 3 (NCI-Common Terminology Criteria for Adverse Events, vs. 3.0) was assessed in patients with upper rectal cancer (inferior tumor margin ≥ 12 cm above the anal verge) treated with upfront surgery and 5-Fluorouracil (5-FU) based adjuvant chemotherapy (CTx).

Methods: 75 participants of the GAST-05-phase-IIb-trial (ISRCTN35198481) were tested in this single center analysis for DPYD*2A-wildtype (WT) at staging. After surgery, 43 patients (stages II and III, according to the current 8th TNM/UICC-classification, 2017) received FOLFOX-CTx and entered follow-up (median: 101 months). According to recent recommendations of the European Medicines Agency (EMA) and national guidelines, post-hoc genotyping for DPYD*2A (c.1905 + 1G > A; IVS14 + 1G > A; rs3918290), DPYD*13 (c.1679T > G; rs55886062), polymorphism c.2846 A > T (rs67376798) and Haplotype B3 (HapB3) (c.1236G > A; c.1129-5923 C > G) was performed using cryopreserved blood samples and standardized PCR-techniques.

Results: Five patients were found to have a heterozygous (het_) DPYD-HapB3-status. Across all patients, the adherence to CTx-cycles 1 to 4 was 100%, 97.7%, 95.3%, and 93.0%, respectively. Grade ≥ 3 CTC-AEs were observed in 0.9% of both het_HapB3- and WT-patients. The mean administered dose of 5-FU was 68.8% of the target in DPYD-HapB3 carriers, compared to 92.6% in 38 WT patients. Logistic regression analysis revealed that 5-FU dose reductions were significantly associated with DPYD-HapB3 carrier status (odds ratio [OR] 12.55, p = 0.044) and male sex (OR 0.23, p = 0.049). During follow-up het_HapB3-patients had a recurrence rate of 60.0%, compared to 13,6% for WT-patients. The disease-free survival (DFS) for het_HapB3-patients was significantly reduced vs. WT (p = 0.010). Multivariable analysis showed that het_HapB3-patients had an increased risk for reduced DFS (HR 3.774; p = 0.057). Interestingly, 5-FU dose reductions per se were not significantly associated with limited DFS in the total population.

Conclusion: DPYD genotyping revealed a het_HapB3 variant in 11.6% of DPYD*2A-WT patients treated with FOLFOX. While not linked to increased toxicity, HapB3 status was associated with reduced DFS, suggesting an impact on treatment efficacy. These results support DPYD genotyping and highlight the need for adequate 5-FU plasma level assessment followed by subtile dose escalation (therapeutic drug monitoring) to personalize 5-FU dosing more precisely, safely and most effective.

Purpose: The high-dose methotrexate (MTX) regimen is a first-line treatment for primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). However, MTX-related kidney injury is a severe treatment complication. No cases of capillary leak syndrome (CLS) causing delayed MTX metabolism-associated renal failure have been reported.

Case presentation: A 48-year-old female presented to Zibo Central Hospital in April 2024 with headaches. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed a space-occupying lesion in the right occipital lobe. A stereotactic biopsy was performed to determine the nature of the lesion. Postoperative pathology confirmed DLBCL. The patient underwent a TZM regimen, which included Tislelizumab, MTX, and Zanubrutinib. On the first day following MTX, the patient developed generalized edema, shortness of breath, and reduced urine output. Laboratory tests revealed hypoxemia, low albumin levels, and acute kidney injury. Based on these findings, the patient was diagnosed with CLS. To quickly lower the blood MTX concentration, pleural effusion drainage and continuous renal replacement therapy (CRRT) were performed. The treatment was successful, and the patient recovered and was discharged.

Conclusion: CLS is a serious complication for DLBCL patients receiving high-dose MTX therapy.

Background: Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine.

Objective: We aimed at evaluating the protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal cancer (CRC).

Methods: In this randomized controlled parallel study, 44 newly diagnosed patients with stage II CRC were randomly allocated into two groups; Group 1(control group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) and group 2 (celecoxib group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) in addition to 200 mg of oral celecoxib twice daily for 14 days of the 3-week cycle. At baseline and after the 6th chemotherapy cycle the patients' quality of life (QOL) was assessed using hand and foot syndrome (HFS) specific QOL questionnaire (HFS-14). Moreover, blood samples were collected in order to evaluate the serum levels of cyclooxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) and malondialdehyde (MDA). Data was analysed using paired and un-paired t-tests.

Results: At the end of the study and as compared to control group, celecoxib treated group showed significantly lower incidence of HFS (P = 0.015). Additionally, celecoxib treated group showed significant decline in the serum levels of TNF-α (P = 0.016) and MDA (P = 0.014) which was associated with non-significant difference in the serum level of COX-2 between the two groups (P = 0.476). Celecoxib was safe and well-tolerated throughout the study period.

Conclusion: Celecoxib may represent a potential protective agent against capecitabine induced hand and foot syndrome in patients with colorectal cancer.

Purpose: Antiangiogenic tyrosine kinase inhibitors (TKIs) are associated with elevated hemoglobin [Hb] levels, potentially influencing prognosis in advanced hepatocellular carcinoma (HCC) patients. However, the impact of altitude on Hb dynamics and its prognostic significance remains underexplored. This study aimed to assess altitude-related Hb changes and their relationship with treatment outcomes in patients following TKI treatment.

Methods: In this retrospective cohort study, medical data from two institutions in Tibet and Beijing were analyzed. Between 2016 and 2022, 128 advanced HCC patients treated with antiangiogenic TKIs were divided into high- and low-altitude groups based on their city of residence. Hematological parameters were retrieved at baseline and every 3 months for 9 months post-treatment initiation. Propensity score matching (PSM) was used to adjust for demographic and baseline differences. Hb percentage changes from baseline (no increase, increase < 15%, increase ≥ 15%) were evaluated at each time point as predictors of time to treatment failure (TTTF) using the Cox proportional hazards model.

Results: After PSM, Hb trajectories differed between the altitude groups. The high-altitude patients exhibited progressive increases, while the low-altitude patients experienced a transient rise followed by a decline. We found no significant TTTF differences between the matched altitude groups (P = 0.33). However, in the high-altitude unmatched cohort, a ≥ 15% increase in Hb at 9 months was linked to a significantly lower risk of treatment failure (HR = 0.22 [95% CI = 0.06-0.83]; P = 0.03). Patients with increases < 15% showed a numerical trend toward prolonged TTTF (HR = 0.30 [0.08-1.15]).

Conclusion: Antiangiogenic TKIs induce altitude-dependent Hb changes, with sustained increases at high altitudes and transient reversibility at low altitudes. A ≥ 15% increase in Hb at 9 months after TKI therapy may serve as a potential biomarker for identifying high-altitude populations likely to benefit more from TKI therapy. Future studies should validate these findings in larger cohorts.

The BRN2 transcription factor controls the protein expression involved in cell motility and is overexpressed in melanoma. Gene mutations involved in cell signaling pathways lead to BRN2 overexpression, tumor formation and metastasis. Peptides derived from the DNA binding domain of transcription factors can compete for the transcription binding and regulate protein expression. In this work, the antitumor activity in vitro and in vivo of the peptide E24G, derived from the DNA-binding POU domain of the BRN2 transcription factor was investigated. This peptide was fragmented into two smaller peptides E12F and A12G, their antitumor activities were characterized and compared with E24G. The E24G at 1 mM significantly reduced cell motility in vitro of B16F10-Nex2 melanoma cells. E12F peptide also inhibited cell motility at a concentration eight times smaller than E24G in murine and human melanoma cells. We observed that the antitumor activity of both E24G and E12F peptides depends on the macropinocytosis displayed by tumor cells. Also, the E24G and E12F peptides induced an increase of the CDH13 expression in 50%, however the treatment with E12F increased the expression already after 12 h by 100%. In vivo assays showed that both peptides reduced the development of metastatic lung nodules without presenting toxicity to normal organs. Our results indicate that E12F and E24G peptides can restore normal expression of BRN2 target genes at the molecular level, inhibiting the cell motility. In addition, we confirmed that the peptide binds to the DNA binding site of the BRN2 transcription factor. Further studies will elucidate their mechanisms of antitumor activity, so far our results pointed out the potential application of E12F and E24G peptides as innovative treatments for metastatic melanoma.

Purpose: While imatinib is effective for treating Gastrointestinal Stromal Tumors (GISTs), significant variability in patient outcomes exists, highlighting the need for reliable prognostic biomarkers. ETV1, a key transcription factor involved in GIST progression, is implicated in disease biology, but the role of ETV1-related single nucleotide polymorphisms (SNPs) in predicting prognosis remains unclear.

Methods: This study included 75 GIST patients. We focused on identifying tag SNPs in the ETV1 gene and examined their association with clinical outcomes. Patient characteristics, somatic mutations, and imatinib concentration were also analyzed in a multivariate model. ETV1 expression was assessed using immunohistochemistry, and miRNA interactions with ETV1 transcripts were investigated via the dual-luciferase reporter assay system.

Results: We found that the rs3735343 SNP, located in the 3' untranslated region of ETV1, was significantly associated with progression-free survival (PFS) in GIST patients receiving imatinib (P = 0.008). Multivariate analysis identified tumor size (P = 0.032, Hazard Ratio [HR] = 4.173, 95% CI: 1.127-15.454) and rs3735343 (P = 0.009, HR = 8.995, 95% CI: 1.712-47.255) as independent predictors of PFS. The rs3735343 risk allele also correlated with elevated ETV1 expression in GIST tissue (P = 0.04). Additionally, miR-4311 was found to specifically and negatively regulate ETV1 mRNA levels associated with the rs3735343 risk allele in vitro.

Conclusion: This study reported ETV1 rs3735343 as a novel prognostic candidate biomarker for GISTs treated with Imatinib, providing a potential biomarker for risk assessment of GIST. Additionally, our findings suggest that rs3735343 may act as a miRNA-regulated SNP, with miR-4311 playing a key role in its regulation.

Purpose: The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

Methods: This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m². HI was determined by Child-Pugh score. Participants were placed into 1 of the following groups: group 1, moderate HI; group 2, healthy participants matched to group 1; group 3, severe HI; and group 4, healthy participants matched to group 3. Participants received a single dose of fedratinib 300 mg (groups 1 and 2) or 200 mg (groups 3 and 4) and were followed for 21 days.

Results: All participants (N = 38; groups 1, 3, and 4 [n = 8 each], group 2 [n = 14]) completed the trial. Peak and total fedratinib exposures (C_max, AUC_0-∞) were similar between moderate HI versus matched healthy participants. In participants with severe HI, there were lower total exposures compared to the matched healthy participants where the ratios of geometric means for C_max, and AUC_0-∞ were 0.897 and 0.660, respectively, and with large inter-participant variability. Ten participants experienced a treatment-emergent adverse event (all were considered mild), which were evenly distributed across groups.

Conclusion: These data indicate that reducing fedratinib starting doses is not necessary for patients with moderate or severe HI, and support clinicians in regular monitoring of patients with HI taking fedratinib.