Cancer Chemotherapy and Pharmacology最新文献

Purpose: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles.

Methods: Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses.

Results: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%.

Conclusions: The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Purpose: Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity.

Methods: We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000 µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling.

Results: Geometric mean docetaxel clearance was 57.9 L/h (GCV 78.6%) after admission of a millidose and 40.3 L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92).

Conclusion: Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Purpose: In exposure-response analyses of oral targeted anticancer agents, longitudinal plasma trough concentrations are often aggregated into a single value even though plasma trough concentrations can vary over time due to dose adaptations, for example. The aim of this study was to compare joint models to conventional exposure-response analyses methods with the application of alectinib as proof-of-concept.

Methods: Joint models combine longitudinal pharmacokinetic data and progression-free survival data to infer the dependency and association between the two datatypes. The results from the best joint model and the standard and time-dependent cox proportional hazards models were compared. To normalize the data, alectinib trough concentrations were normalized using a sigmoidal transformation to transformed trough concentrations (TTC) before entering the models.

Results: No statistically significant exposure-response relationship was observed in the different Cox models. In contrast, the joint model with the current value of TTC in combination with the average TTC over time did show an exposure-response relationship for alectinib. A one unit increase in the average TTC corresponded to an 11% reduction in progression (HR, 0.891; 95% confidence interval, 0.805-0.988).

Conclusion: Joint models are able to give insights in the association structure between plasma trough concentrations and survival outcomes that would otherwise not be possible using Cox models. Therefore, joint models should be used more often in exposure-response analyses of oral targeted anticancer agents.

Purpose: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC.

Methods: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC.

Results: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs.

Conclusion: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee.

Trial registration numbers: ClinicalTrials.gov : NCT03828799.

Purpose: High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables.

Methods: 517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48 h or ≥ 0.1 µmol/L at 72 h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method.

Results: Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72 h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes.

Conclusion: This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction.

Purpose: Among cases of breast cancer, estrogen receptor-positive (ER +), PIK3CA-mutant, HER2- advanced breast cancer stands as a particularly complex clinical indication where approximately 40% of ER + /HER2- breast carcinomas present mutations in the PIK3CA gene. A significant hurdle in treating ER + breast cancer lies in surmounting the challenges of endocrine resistance. In the clinical setting, a multifaceted approach is essential for this indication, one that not only explores the effectiveness of individual treatments but also delves into the potential gains in therapeutic outcome from combination therapies.

Methods: In the current study, longitudinal tumor growth inhibition (TGI) models were developed to characterize tumor response over time in postmenopausal women with ER + /HER2- advanced or metastatic breast cancer undergoing treatment with fulvestrant alone or in combination with the PI3K inhibitor, taselisib. Impact of clinically relevant covariates on TGI metrics was assessed to identify patient subsets most likely to benefit from treatment with fulvestrant monotherapy or combination with taselisib.

Results: Tumor growth rate constant (K_g) was found to increase with increasing baseline tumor size and in the absence of baseline endocrine sensitivity. Further, K_g decreased in the absence of baseline liver metastases both in fulvestrant monotherapy and combination therapy with taselisib. Overall, additive/potentially synergistic anti-tumor effects were observed in patients treated with the taselisib-fulvestrant combination.

Conclusion: These results have important implications for understanding the therapeutic impact of combination treatment approaches and individualized responses to these treatments. Finally, this work, emphasizes the importance of model informed drug development for targeted cancer therapy.

Clinical trial registration: NCT02340221 Registered January 16, 2015, NCT01296555 Registered February 14, 2011.

Purpose: Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.

Methods: In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.

Results: Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.

Conclusion: RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

Purpose: Colorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response.

Methods: AKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements.

Results: We found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention.

Conclusion: This study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.