Cancer Chemotherapy and Pharmacology最新文献

KRAS was (Kirsten rat sarcoma viral oncogene homolog) revealed as an important target in current therapeutic cancer research because alteration of RAS (rat sarcoma viral oncogene homolog) protein has a critical role in malignant modification, tumor angiogenesis, and metastasis. For cancer treatment, designing competitive inhibitors for this attractive target was difficult. Nevertheless, computational investigations of the protein's dynamic behavior displayed the existence of temporary pockets that could be used to design allosteric inhibitors. The last decade witnessed intensive efforts to discover KRAS inhibitors. In 2021, the first KRAS G12C covalent inhibitor, AMG 510, received FDA (Food and drug administration) approval as an anticancer medication that paved the path for future treatment strategies against this target. Computer-aided drug designing discovery has long been used in drug development research targeting different KRAS mutants. In this review, the major breakthroughs in computational methods adapted to discover novel compounds for different mutations have been discussed. Undoubtedly, virtual screening and molecular dynamic (MD) simulation and molecular docking are the most considered approach, producing hits that can be employed in subsequent refinements. After comprehensive analysis, Afatinib and Quercetin were computationally identified as hits in different publications. Several authors conducted covalent docking studies with acryl amide warheads groups containing inhibitors. Future studies are needed to demonstrate their true potential. In-depth studies focusing on various allosteric pockets demonstrate that the switch I/II pocket is a suitable site for drug designing. In addition, machine learning and deep learning based approaches provide new insights for developing anti-KRAS drugs. We believe that this review provides extensive information to researchers globally and encourages further development in this particular area of research.

Chemoresistance in triple negative breast cancer (TNBC) poses a significant challenge in effective treatment, necessitating the exploration of novel therapeutic strategies. This study evaluates the efficacy of napabucasin, a potent STAT3 inhibitor, in two paclitaxel-resistant TNBC cell models (MD-MBA-231-r and BT-549-r). We observed that napabucasin significantly reduced cell viability and colony formation in a dose-dependent manner. Combination index analysis revealed synergistic interactions between napabucasin and paclitaxel, suggesting enhanced cytotoxic effects when used in combination. Mechanistically, napabucasin inhibited STAT3 signaling and impaired mitochondrial function, as evidenced by decreased phosphorylated STAT3 levels, reduced mitochondrial complex I activity, lower oxygen consumption rate and diminished ATP levels. Further analysis indicated that paclitaxel-resistant cells exhibit higher mitochondrial biogenesis and function compared to their sensitive counterparts, with elevated expression of mitochondrial genes and biogenesis regulators, and increased levels of mitochondrial respiration. In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC.

Purpose: This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL).

Methods: DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing.

Results: Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001).

Conclusion: NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.

Purpose: The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC).

Methods: Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis.

Results: The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021).

Conclusion: A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.

Purpose: This study aimed to evaluate capivasertib exposure-response relationships for clinical safety events to support dosage selection.

Methods: Data from 277 patients with solid tumors participating in three phase 1 studies were analyzed. Capivasertib 80-800 mg was administered as monotherapy orally twice daily (BID) on continuous or intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) schedules. Relationships between exposure related metrics (dose, weekly dose, AUC, AUC_PWD, C_max, and C_min) and probability of safety endpoints (adverse event [AE] leading to dose discontinuation, AE leading to dose modification, serious AE [SAE], AE grade ≥ 3, AE grade ≥ 1, diarrhea AE grade ≥ 2, rash AE grade ≥ 2, hyperglycemia AE grade ≥ 3 and increased blood glucose > 13.9 mmol/L) were evaluated by logistic regression.

Results: Significant exposure-response relationships were identified for all safety endpoints evaluated, except for AE grade ≥ 1. The analysis suggested that most of the safety endpoints are driven by the total weekly exposure, whereas glucose elevations are driven by the exposure achieved within a dosing interval. The probability of experiencing an AE leading to dose discontinuation, AE leading to dose modification, SAE, AE grade ≥ 3, diarrhea or rash were lower with the 480 mg BID [4/3] schedule than with the 320 mg BID continuous schedule.

Conclusion: Significant exposure-response relationships were identified for safety endpoints when capivasertib was administered to patients with solid tumors suggesting that the intermittent [4/3] schedule is better tolerated than the continuous schedule due to lower total weekly exposure.

Purpose: The aim of this study was to evaluate plasma and bone- and soft-tissue concentrations of doxorubicin following two administrations of either bolus or continuous infusion administered at a three-week interval. The achievement of adequate concentration at target sites is believed to be positively correlated to effect, and it has been suggested that concentrations are affected by the number of administrations.

Methods: Eighteen female pigs were included in the study and randomized into two groups of nine receiving either a bolus or continuous infusion. The animals received a dosage of 2 mg/kg on day 1 and on day 22. From day 1 to 10, doxorubicin concentrations, as well as kidney and liver function, were monitored with plasma samples (total concentrations). On day 22, doxorubicin was measured in plasma samples (total concentration) and microdialysates (unbound concentrations) from subcutaneous tissue, muscle, synovial fluid of the knee joint, cancellous bone, and intravenously.

Results: On day 22, the pharmacokinetic profiles were comparable between the two groups except for plasma AUC_{0 - 12 h}, which was higher after continuous infusion, and intravenous C_max, which was higher after bolus infusion. Bone- and soft tissue concentrations were below 0.10 µg/mL. Except for mean plasma (total) concentration at the 6 h timepoint on day 1 and 22 in the continuous group, which was higher after the first administration (p = 0.037), no differences in plasma concentrations were found between the two administrations.

Conclusion: Low mean tissue doxorubicin concentrations and similar pharmacokinetic profiles were found between the bolus and continuous infusion groups. Thus, similar anti-neoplastic efficacy is to be expected with both administration types.

Purpose: Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics.

Methods: This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL).

Results: Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0.

Conclusion: We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

Purpose: To explore the possibility of treating patients with alternative imatinib formulations.

Methods: Two patients were treated with different enteral en rectal imatinib formulations. During treatment plasma concentrations where measured to assure adequate exposure.

Results: The first patient received imatinib suspension through the duodenum tube. With a dose of 400 mg BID the patient had an imatinib plasma concentration of 750 µg/L. After increasing the dose to 600 mg BID the imatinib plasma concentration was 1500 µg/L (target GIST treatment > 1100 µg/L). Rectal administration of the tablet did not lead to sufficient plasma concentrations. The second had adequate exposure of imatinib both when the suspension was taken orally and through the tube (target CML treatment are > 1000 µg/L).

Conclusion: For patients able to swallow liquids, we prefer the suspended imatinib tablets (comparable to drug label). If patients have a duodenum tube the use of a suspension base with pulverized tablets could be an alternative. Based on the extremely low exposure found in case 1, we do not recommend rectal administration of tablets. We recommend the monitor plasma concentrations when off label dosing forms are used.