Cancer Chemotherapy and Pharmacology最新文献

Purpose

We investigated the inhibitory effect of edaravone (EDR) lotion on chemotherapy-induced alopecia (CIA) to improve the quality of life for patients with cancer.

Methods

Wistar rats were intraperitoneally injected with cyclophosphamide (CPA, 75 mg/kg) to induce CIA and divided into six groups: (1) Control; (2) EDR 0%; (3) EDR 0.3%; (4) EDR 3%. The TUNEL-positive area was examined histologically, and mRNA expression levels of the apoptosis-related factors, such as B-cell/CLL lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax), were determined.

Results

In the three CPA-treated groups, a decrease in the coverage score (percentage of hairs covered) was observed from days 16 to 18. In addition, coverage scores on day 21, the last day of observation, showed a tendency for the suppression of hair loss to increase, though hair loss was observed in all groups. The coverage scores of the EDR 0.3% and 3% groups after day 17 were significantly higher than those of the EDR 0% group. The TUNEL-positive area of skin tissue on day 16 was extensive in the EDR 0% group and decreased in the EDR 0.3% and 3% groups. The mRNA expression ratio of Bcl-2/Bax on day 21 was maintained at the same level as that of the control group only in the EDR 3% group.

Conclusion

This study confirmed the use of EDR lotion to inhibit hair loss, indicating that the clinical application of EDR lotion may improve the quality of life for patients with cancer and their willingness to undergo treatment.

Purpose

Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug–drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors.

Methods

Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted.

Results

Capivasertib–midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUC_inf and C_max was 1.13 (0.97–1.32) and 1.15 (0.99–1.33) for day 8 versus day 1, and 1.75 (1.50–2.05) and 1.25 (1.08–1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment.

Conclusion

The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population.

ClinicalTrials.gov: NCT04958226.

Purpose

Tyrosine kinase inhibitor (TKI) resistance is the main type of drug resistance in lung cancer patients with epidermal growth factor receptor (EGFR) mutations, but its underlying mechanism remains unclear. The purpose of this work was to investigate the mechanism by which PARP1 regulates EGFR-TKI resistance to identify potential targets for combating drug resistance.

Methods

The GEO databases, TCGA databases, western blot and qPCR studies were used to investigate the expression of PARP1 in lung cancer cells and tissues and its correlation with the prognosis of lung cancer. The expression of PARP1 in lung cancer TKI resistant cell PC9-ER and TKI sensitive cell PC9 was analyzed by qPCR and western blot. After knocking down of PARP1, CCK-8 assays, colony formation, flow cytometry were used to investigate its impact on erlotinib sensitivity, cell survival, cell cycle, and apoptosis. RNA-seq was used to investigate the mechanism by which PARP1 participates in EGFR-TKI resistance, and the results were validated in vitro and in vivo studies.

Results

PARP1 was highly expressed in both lung cancer tissues and cells. Subsequently, increased PARP1 expression was observed in PC9-ER compared with its parental cell line. Knockdown of PARP1 increased erlotinib sensitivity, promoted cell apoptosis, and suppressed cell growth. RNA-seq and previous studies have shown that the PI3K/AKT/mTOR/P70S6K pathway is involved in PARP1-mediated TKI resistance, and these results were confirmed by Western blot in vitro and in vivo.

Conclusion

PARP1 may serve as a potential therapeutic target for reversing EGFR-TKI resistance in NSCLC via the PI3K/AKT/mTOR/P70S6K pathway.

Purpose

This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs).

Methods

We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H₂-receptor antagonists (H₂RAs).

Results

A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34–2.27), 1.33 (0.80–2.22), 1.73 (0.89–3.36), and 5.04 (1.38–18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively.

Conclusion

In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement. Fifty-eight participants received treatment. Total exposure to fedratinib was similar after oral administration of intact capsules or when dispersed in a nutritional supplement (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration geometric mean ratio [AUC_0-t GMR] [90% CI], 1.007 [0.929-1.092]). Total exposure to fedratinib was slightly reduced following nasogastric administration (AUC_0-t GMR 0.850 [0.802-0.901]) and as a divided dose (AUC_0-t GMR 0.836 [0.789-0.886]). No new safety signals were identified for fedratinib, and most participants found the taste and palatability acceptable when dispersed in a nutritional supplement. Overall, results suggest no clinically meaningful differences in total exposure to fedratinib between the tested oral administration methods. These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).

We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the "CysPed equation"). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units.

Purpose: Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study.

Methods: Dose escalation evaluated eftozanermin alfa monotherapy 2.5-15 mg/kg on Day 1 or Days 1/8 of a 21-day cycle. Dose optimization evaluated eftozanermin alfa monotherapy or combination therapy with either oral venetoclax 400-800 mg daily (eftozanermin alfa 1.25-7.5 mg/kg Days 1/8/15 of a 21-day cycle) or chemotherapy (eftozanermin alfa 3.75 or 7.5 mg/kg Days 1/8/15/22 of a 28-day cycle and FOLFIRI regimen [leucovorin, 5-fluorouracil, and irinotecan] with/without bevacizumab on Days 1/15 of a 28-day cycle).

Results: Systemic exposures (maximum observed concentration [C_max] and area under the concentration-time curve [AUC]) of eftozanermin alfa were approximately dose-proportional across the entire dose escalation range with minimal to no accumulation in Cycle 3 versus Cycle 1 exposures. Comparable exposures and harmonic mean half-lives (35.1 h [solid tumors], 31.3 h [hematologic malignancies]) were observed between malignancy types. Exposures (dose-normalized C_max and AUC) in Japanese subjects were similar to non-Japanese subjects. Furthermore, eftozanermin alfa/venetoclax combination therapy did not have an impact on the exposures of either agent. Treatment-emergent anti-drug antibodies were observed in 9.4% (13/138) of subjects.

Conclusions: The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa.

Trial registration id: NCT03082209.

Background: Burkitt's lymphoma, one of the most common subtypes of pediatric malignant lymphoma, is notorious for its swift onset, aggressive proliferation, pronounced invasiveness, and marked malignancy. The therapeutic landscape for Burkitt's lymphoma currently falls short of providing universally effective and tolerable solutions. Andrographolide, a primary active component of Andrographis paniculata, is renowned for its properties of heat-clearing, detoxification, inflammation reduction, and pain relief. It is predominantly used in treating bacterial and viral infections of the upper respiratory tract, as well as dysentery. Various reports highlight the antitumor effects of andrographolide. Yet, its specific impact and the underlying mechanism of action on Burkitt's lymphoma remain an uncharted area of research.

Method: We employed network pharmacology to pinpoint the targets of andrographolide's action on Burkitt's lymphoma and the associated pathways. We then evaluated the impact of andrographolide on Burkitt's lymphoma using both in vitro and in vivo patient-derived xenograft (PDX) models. Concurrently, we confirmed the molecular targets of andrographolide in Burkitt's lymphoma through immunofluorescence assays.

Result: Utilizing network pharmacology, we identified 15 relevant targets, 60 interrelationships between these targets, and numerous associated signaling pathways for andrographolide's action on Burkitt's lymphoma. In vitro efficacy tests using High-throughput Drug Sensitivity Testing and in vivo PDX model evaluations revealed that andrographolide effectively curtailed the growth of Burkitt's lymphoma. Moreover, we observed a increased in the expression of JUN (c-Jun) and CASP3 (Caspase 3) proteins in Burkitt's lymphoma cells treated with andrographolide.

Conclusion: Andrographolide inhibits the growth of Burkitt's lymphoma by inhibiting JUN and CASP3 proteins.

Purpose: Acneiform rash is frequently observed in patients undergoing cancer treatment with anti-epidermal growth factor receptor (EGFR) antibody drugs and can often necessitate treatment discontinuation. However, the specific changes in skin parameters resulting from anti-EGFR antibody drug administration are poorly understood. Therefore, this study aimed to longitudinally and quantitatively evaluate the changes in skin parameters (transepidermal water loss [TEWL], hydration level, and sebum level) caused by anti-EGFR antibody drugs and investigate their potential as control markers for skin disorders.

Methods: This prospective study included 12 patients with colorectal cancer who received anti-EGFR antibody drugs for the first time. The assessment items included the grade of acneiform rash and skin parameters (TEWL, hydration level, and sebum level), which were observed for up to 6 weeks after administration of the medication.

Results: The enrolled patients were classified into two groups based on the grade of acneiform rash caused by anti-EGFR antibody drugs: "Grade 1 and lower," and "Grade 2 and higher." The skin parameters were compared between these groups. The results showed that in the "Grade 2 and higher" group, TEWL in the face (at week 2 of administration), chest (baseline, weeks 2 and 6 of administration), and back (at week 2 of administration) were significantly higher than those in the "Grade 1 and lower" group. However, the two groups showed no significant differences in hydration or sebum levels at any time point.

Conclusion: TEWL can serve as a marker for acneiform rashes induced by anti-EGFR antibody drugs during cancer treatment.

Purpose: CUDC-907 is a promising dual-target inhibitor of the HDAC and PI3K signaling pathways, with demonstrated therapeutic effects in a range of malignant tumors. However, its potential application in ovarian cancer (OC) has not been fully explored yet. In this study, we sought to investigate the efficacy of CUDC-907 in treating OC, both in vitro and in vivo.

Methods: Here, we examined the correlation between PI3K or HDAC expression and the prognosis of OC patients using the GEPIA database. RNA-Seq analysis was performed on OC cells treated with CUDC-907.To assess various cellular processes, including proliferation, migration, invasion, apoptosis, and cell cycle, we performed a series of assays, including the CCK8, EDU, wound healing, cell invasion, and flow cytometry assays. Real-time quantitative PCR and western blotting were performed to measure the expressions of target genes. Additionally, we utilized the SKOV3 xenograft tumor model to investigate the inhibitory effects of CUDC-907 on tumor growth in vivo.

Results: Bioinformatics analyses revealed that up-regulated HDAC and PI3K were significantly correlated with patients' poor survival in OC. In vivo and in vitro experiments have demonstrated that CUDC-907 could inhibit the proliferation of OC cells by inhibiting the PI3K and HDAC pathways to down-regulate the expression of c-Myc, and induce cell apoptosis by inhibiting the PI3K/AKT/Bcl-2 pathway, and up-regulate p21 to induce G2 /M phase arrest.

Conclusion: Our results showed that CUDC-907 had powerful anti-tumor effects on OC, which could provide a theoretical and experimental basis for the application of CUDC-907 in the therapy of OC.