Cancer Chemotherapy and Pharmacology最新文献

Purpose: Human epidermal growth factor-2 (HER-2) targeted drugs are used in only HER-2 overexpressed cancers. However, only a small portion of these cancer types are HER-2 overexpressed. In this study, we aimed to upregulate HER-2 receptors in MCF-7 breast cancer and HT-29 colon cancer cell cultures, which these cells are not HER-2 upregulated in natural status.

Methods: We used a 10-day non-cytotoxic lapatinib dose to upregulate HER-2 receptors. HER-2 levels of these cell lines were tested with ELISA and immunofluorescence tests before and after 10 days of lapatinib administration. After upregulation of HER-2, we administered trastuzumab, and T-DM1 to these cell lines to observe whether there is an increase in anticancer activity. We used a cell viability test to show the cytotoxicity of trastuzumab and T-DM1. Also, we used ELISA and immunofluorescence for HER-2 pathway proteins to understand the mechanism of increased anti-cancer activity.

Results: We showed that administration of lapatinib for 10 days leads to overexpression of HER-2 receptors on both MCF-7 and HT-29 cells. A significant increase in the cytotoxicity of trastuzumab or T-DM1 was observed after 10 days of lapatinib administration.

Conclusion: We named this method the smash method, which is the volleyball term. In volleyball, the ball is raised while low and quickly hits the ground again, just like we do with the HER-2 receptor. The smash method can switch HER-2 negative or HER-2 low tumors into HER-2 overexpressed, iatrogenically. Thus, we can use her2-targeted therapies in all cancer patients instead of a small portion.

Purpose: Cisplatin (CDDP) induces acute kidney injury (AKI) as a side effect during neoadjuvant chemotherapy (NAC). Urinary vanin-1 excretion may increase during CDDP treatment. We investigated whether urinary vanin-1 is an early biomarker for CDDP-induced AKI.

Methods: Thirty patients were administered 80 mg/m² CDDP on day 1 as NAC for esophageal cancer. Blood and urine samples were collected on days 1, 2, 3, 4, and 6 after CDDP administration. Serum creatinine (sCr) and urinary vanin-1 levels were measured. Creatinine clearance (cCr) and estimated glomerular filtration rate (eGFR) were calculated from sCr. Based on the change in sCr after CDDP administration, the AKI and non-AKI groups were defined using the Kidney Disease Improving Global Outcomes classification. Changes in sCr, cCr, eGFR, and urinary vanin-1 levels were compared between the two groups.

Results: A gradual increase in sCr and a decrease in eGFR were observed over time post-CDDP administration, with differences between the two groups becoming significant by day 4. However, urinary vanin-1 levels increased on day 3 after CDDP administration, and the difference between the two groups was significant on day 3. Receiver operating characteristic curves of urinary vanin-1 on day 3 revealed that a cut-off value of 3.17 ng urinary vanin-1/mg urinary creatinine yielded an area under the curve, sensitivity, and specificity of 0.83 (P < 0.05), 75.0%, and 22.7%, respectively. The non-AKI incidence below the cut-off value of urinary vanin-1 of 3.17 ng/mg uCr was 89.5%.

Conclusion: Urinary vanin-1 is a superior minimally invasive biomarker for the early prediction of CDDP-induced AKI.

Purpose: The treatment landscape for chronic myeloid leukemia (CML) has been revolutionized by the introduction of imatinib, a tyrosine kinase inhibitor, which has transformed the disease from a fatal condition into a manageable chronic illness for a substantial number of patients. Despite this, some individuals do not respond adequately to the treatment, and others may experience disease progression even with continued therapy. This study examined how CYP2C8*3 (G416A; rs11572080) and ABCG2 C421A (rs2231142) single nucleotide polymorphisms (SNPs) affect the plasma trough concentration and therapeutic response of imatinib in Egyptian CML patients.

Methods: The study included fifty patients with chronic-phase CML, who were categorized into two groups: responders (n = 26) and non-responders (n = 24), according to their BCR-ABL1 transcription levels after 12 months of imatinib treatment. Genotyping of the CYP2C8*3 and ABCG2 C421A polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while plasma trough concentrations were determined through high-performance liquid chromatography with ultraviolet-diode array detection (HPLC-UV/DAD).

Results: Patients with the CA genotype of ABCG2 C421A showed significantly higher mean plasma trough concentrations of imatinib (CA: 1731 ± 424.7 ng/mL; CC: 1294 ± 381.3 ng/mL; p = 0.0132) and demonstrated a better molecular response compared to those with the CC genotype (p = 0.0395).

Conclusion: The ABCG2 C421A polymorphism significantly influenced imatinib plasma trough concentrations and molecular responses in Egyptian chronic-phase CML patients. Genotyping of this polymorphism in these patients could assist in optimizing imatinib therapy, predicting more favorable treatment outcomes, and enabling the development of more personalized treatment plans.

Objectives: The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance.

Patients and methods: This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database.

Results: We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values.

Conclusion: Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.

Objective: This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [¹⁴C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.

Methods: Plasma, urine, and feces were collected post [¹⁴C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism.

Results: The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4.

Conclusion: Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.

Purpose: The associations between first dose reduction or interruption by side effects and lenvatinib plasma trough concentration (C₀) after administration of a starting dose of 24 mg in 70 Japanese patients with thyroid cancer were evaluated.

Methods: Plasma samples were collected each week for 1 month and at the first incidence of side effects leading to dose reduction or interruption after beginning administration of 24 mg lenvatinib.

Results: The area under the receiver operating characteristic curve was 0.789 at a lenvatinib C₀ threshold of 128.25 ng/mL for predicting the first dose reduction or interruption. The median time to the first dose reduction or interruption was 14.0 days in patients with a C₀ of ≥ 128.25 ng/mL and 21.0 days in those with a C₀ of < 128.25 ng/mL (P = 0.001). At one, two, three and four weeks respectively, the first dose reduction or interruption was associated with body weight (P = 0.034); sex (P = 0.021); sex, age, and lenvatinib C₀ of ≥ 128.25 ng/mL (P = 0.025, 0.024, and 0.048, respectively); and age and lenvatinib C₀ of ≥ 128.25 ng/mL (each P = 0.004).

Conclusions: On day 8 after administration of 24 mg lenvatinib, lenvatinib dose may be adjusted based on the target C₀ of 128.25 ng/mL to maintain a high dose intensity during this early phase; however, because persistence of a higher C₀ of 128.25 ng/mL causes early dose interruption or reduction, prospective dose reduction based on the next lower target C₀ for the maintenance phase may be necessary.

Progressive leptomeningeal metastases (LM) are associated with intractable neurological symptoms and a poor prognosis, and effective treatment options are limited. Intrathecal (IT) pemetrexed has been shown to confer clinical benefit in lung adenocarcinoma, yet our understanding of the efficacy and safety of the treatment is limited. We report a patient with a long-standing history of leptomeningeal disease due to ALK-positive adenocarcinoma of the lung, previously controlled by increased doses of lorlatinib (125 mg/day). Rapid LM progression prompted the start of IT pemetrexed, after which the patient experienced immediate clinical improvement. The case provides additional support that IT pemetrexed can offer symptomatic relief and may be considered as a treatment option in advanced LM. Furthermore, the case illustrates that an increased dose of lorlatinib may efficiently control LM in patients with ALK-rearranged NSCLC, following progression on standard lorlatinib dosage.

Background: The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.

Methods: We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed.

Results: 19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance.

Conclusions: Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.

Clinical trial registration: NCT02595879.

Purpose: The study aims to investigate the absorption, metabolism, and excretion of donafenib, a deuterated derivative of sorafenib, in healthy Chinese male volunteers.

Methods: Six healthy Chinese male volunteers were administered a single oral dose of 300 mg donafenib containing 120 µCi of [14 C]-donafenib. The study involved collecting and analyzing plasma, urine, and feces samples to determine the recovery and distribution of total radioactivity, identify metabolites, and assess the metabolic pathways of donafenib.

Results: The mean recovery of total radioactivity was 97.31% of the administered dose. Six metabolites were identified, with the parent drug being the major radioactive component in plasma (67.52% of total radioactivity) and feces (83.17% of the dose). The N-oxidation metabolite (M2) was prominent in plasma. Donafenib was predominantly excreted via feces, indicating liver metabolism, with minimal renal excretion. The metabolic pathways of donafenib were similar to those of sorafenib, but the metabolite profiles differed significantly. Notably, the amide hydrolysis metabolite M6, present in sorafenib, was absent in donafenib.

Conclusion: Donafenib is primarily metabolized in the liver and excreted through feces, with a metabolic profile that differs from sorafenib due to the deuterium isotope effect. These differences in metabolic characteristics may contribute to donafenib's improved safety and efficacy as a treatment for advanced hepatocellular carcinoma (HCC).

Purpose: Osteolysis is a common complication in patients with multiple myeloma (MM). Our previous studies have demonstrated that MM cells can promote osteoclast differentiation of macrophages. In this study, we explored the effect of sulforaphane (SFN), a natural NRF2 activator found in broccoli, on MM cell-induced osteoclast differentiation.

Methods: Conditional medium (CM) derived from MM cells was used to induce osteoclast differentiation, and TRAP staining was performed to examine osteoclast. Gene expression was detected by western blotting or real-time PCR. Cell counting and EdU staining were performed to test macrophage proliferation.

Results: We showed that the CM of MM cells downregulated the expression of ferroportin1 (Fpn1), the only known iron exporter in vertebrate cells, thereby increasing cellular iron levels in murine macrophage cells RAW264.7. Deferoxamine (DFO), an iron chelator, effectively blocked MM cell CM-induced osteoclast differentiation and macrophage proliferation, suggesting that iron overload played a key role in these cellular events. Subsequent mechanistic investigations revealed that MM cell CM induced osteoclast differentiation and macrophage proliferation by activating the JNK/AP-1/NFATC1 pathway and PI3K/AKT pathway. SFN was found to increase Fpn1 expression, leading to decreased cellular iron levels in RAW264.7 cells activated by MM cell CM. Importantly, the osteoclast differentiation and macrophage proliferation induced by MM cell CM were significantly inhibited by SFN.

Conclusion: Altogether, our findings indicated that SFN inhibits MM cell-induced osteoclast differentiation and macrophage proliferation by elevating FPN1 levels. SFN could be a promising therapeutic strategy for MM-associated osteolysis.