Cancer Chemotherapy and Pharmacology最新文献

Purpose: Etoposide, together with cisplatin, is a cornerstone in the treatment of metastatic testicular cancer, but dosing can be challenging in patients with organ dysfunction and/or polypharmacy. We report a patient with cystic fibrosis, liver cirrhosis and preexisting pancytopenia grade 1, requiring multiple concomitant medications inhibiting CYP3A4 and P-gp, who presented with metastatic seminoma. METHOD AND RESULTS: Due to potential drug-drug interactions and liver cirrhosis, the initial etoposide dose was reduced to 50% of standard. Monitoring of etoposide plasma concentrations showed that total exposure was not enhanced. The subsequent dose was increased to 100% and further adjusted based on tolerability. After a dose reduction from cycle 2 due to pancytopenia grade 4, the patient successfully completed the chemotherapy regimen and had a complete response on first evaluation.

Conclusion: This case shows that monitoring of etoposide plasma concentrations can be beneficial in complex clinical scenarios involving organ dysfunction and/or potential drug-drug interactions. This is especially important in curative treatment to avoid under dosing. This case report highlights the challenges of dosing etoposide in a patient with cystic fibrosis and liver cirrhosis who is taking multiple drugs that may interact with etoposide. The patient should be monitored closely on how the treatment is tolerated and the dose should be adjusted accordingly.

Oral squamous cell carcinoma is the most common oral malignancy and poses a major health challenge because of late-stage diagnosis, high recurrence, and resistance to treatment. In addition to genetic mutations, oral squamous cell carcinoma is strongly influenced by epigenetic alterations, including abnormal DNA methylation, histone modifications, and dysregulated non-coding RNAs. These changes contribute to the inhibition of tumor suppressor genes and regulation of oncogenic pathways, which promote cancer progression. Oxidative stress and excessive reactive oxygen species further drive these epigenetic changes, creating a vicious cycle that fuels carcinogenesis. Natural antioxidants, including genistein, epigallocatechin gallate, resveratrol, lycopene, and quercetin, have shown promise in preventing and treating oral squamous cell carcinoma. Their multi-targeted actions involve the inhibition of DNA methyltransferases, reversal of tumor suppressor gene promoter hypermethylation, regulation of histone acetylation and methylation, and regulation of microRNAs (miRNAs) that suppress oncogene activity. These compounds restore normal gene function with low toxicity to healthy cells, making them appealing candidates for personalized therapy. By targeting both oxidative stress and epigenetic instability, natural antioxidants offer a promising strategy against the core mechanisms of oral squamous cell carcinoma. Understanding this molecular interplay may employ more effective prevention and therapeutic approaches in future oral squamous cell carcinoma management paradigms.

Cellular senescence is a double-edged sword in cancer biology, initially acting as a tumor-suppressive mechanism but later contributing to cancer progression and therapy resistance. Senescent cells, characterized by stable cell cycle arrest, secrete a complex array of bioactive molecules known as the senescence-associated secretory phenotype (SASP), which fosters chronic inflammation, disrupts tissue architecture, and promotes tumorigenesis through paracrine signaling. Accumulation of these cells in the tumor microenvironment can enhance malignancy, drive metastasis, and impair treatment outcomes. Senotherapeutics, have emerged as promising strategies for targeting senescent cells in cancer therapy. These agents selectively induce apoptosis in senescent cells while preserving normal tissues, representing a paradigm shift in oncology. Senotherapeutics can function as standalone treatments by clearing senescent tumor cells or as adjuvants to chemotherapy and radiotherapy, effectively eliminating residual therapy-induced senescent cells that may contribute to relapse. This dual approach allows for reduced treatment toxicity, improved therapeutic efficacy, and decreased tumor recurrence. Furthermore, targeting non-cancerous senescent cells may help suppress inflammation-driven tumorigenesis, slow disease progression, and enhance patient outcomes. Despite their promise, challenges remain in optimizing senotherapeutic strategies, identifying precise biomarkers, and minimizing off-target effects. This review explores the mechanisms of cellular senescence, its role in tumor dynamics, and the potential of senotherapeutics as a novel adjunct in cancer treatment. By integrating senotherapeutics with existing modalities, the field moves closer to more effective, personalized cancer interventions, warranting further preclinical and clinical investigation.

Purpose: Bispecific antibody-drug conjugates (BsADCs) represent a promising strategy to overcome limitations of conventional ADCs in breast cancer, such as tumor heterogeneity and inefficient internalization. This review summarizes recent advances and the therapeutic potential of BsADCs.

Methods: We conducted a literature review, focusing on BsADC candidates selected for clinical relevance (e.g., ZW49, BL-B01D1), mechanistic innovation (e.g., biparatopic targeting, engaging fast-internalizing receptors), and potential in challenging subtypes like triple-negative breast cancer (TNBC).

Results: BsADCs enhance drug delivery through dual targeting. Biparatopic HER2-targeting agents (e.g., ZW49, JSKN003) induce receptor clustering and robust internalization. BsADCs co-engaging rapidly internalizing receptors (e.g., HER2×CD63) hijack efficient endocytic pathways, showing activity even in low HER2-expression models. Furthermore, BsADCs targeting compensatory pathways, such as EGFR×HER3 (BL-B01D1) and TROP2×HER3 (JSKN016), have demonstrated breakthrough efficacy in TNBC. Optimization of linker technology and drug-to-antibody ratio (DAR) has improved stability and the therapeutic window, enabling the progression of several BsADCs into Phase III trials.

Conclusion: BsADCs are a transformative therapeutic modality for breast cancer. Their ability to enhance tumor selectivity, overcome heterogeneity, and target resistant pathways positions them as key players in the future oncology landscape, with ongoing trials poised to define their clinical role.

Purpose: Anthracycline-based chemotherapy with doxorubicin plus cyclophosphamide (AC) is commonly used for breast cancer during the second and third trimesters of pregnancy, yet pharmacokinetic data for these drugs in pregnant patients are limited. This case report evaluates changes in the plasma concentrations of doxorubicin and cyclophosphamide during pregnancy in a breast cancer patient undergoing AC to clarify the influence of gestation on drug pharmacokinetics.

Methods: A 39-year-old woman with stage IIA breast cancer diagnosed at 16 weeks of gestation received four cycles of AC, with doses based on her pre-pregnancy body surface area. Plasma concentrations of doxorubicin and cyclophosphamide were measured by LC-MS/MS 24 h after administration during the first and third cycles.

Results: Doxorubicin concentrations were 5.5 and 8.2 ng/mL in the first and third cycles, respectively, which were lower than reported in non-pregnant patients. Cyclophosphamide concentrations were respectively 1.3 and 1.1 µg/mL, which were comparable to non-pregnant levels. No serious maternal or fetal adverse events were observed, and plasma concentrations remained stable over time.

Conclusion: Doxorubicin concentrations during pregnancy were 30%-60% lower than those reported in non-pregnant patients. We did not observe a gestational decline in doxorubicin concentrations between the two sampling points in this patient, likely due to gestational changes in factors that can influence pharmacokinetic parameters (e.g., persistent P-glycoprotein upregulation). Cyclophosphamide pharmacokinetics remained unchanged. Although further studies are needed to confirm the optimal dosing and safety, these findings suggest that AC with pre-pregnancy body surface area-based dosing may be feasible in pregnant patients.

Hypoxia signaling governs angiogenesis, erythropoiesis, and cellular metabolism; its dysregulation via stabilized hypoxia-inducible factors (HIFs) is a shared driver across cancers. In genitourinary oncology, loss of VHL hardwires HIF-2α activity in clear-cell renal cell carcinoma (ccRCC) and across the VHL tumor spectrum. Belzutifan, which blocks HIF-2α-ARNT dimerization, is the first approved transcription-factor inhibitor in a solid tumor and the first medical therapy for a hereditary kidney-cancer syndrome (VHL). This review consolidates 2023-2025 advances: phase III validation in post-IO/TKI ccRCC (progression-free survival and response-rate gains vs. everolimus), durable first-line activity with cabozantinib, and approval for advanced pheochromocytoma/paraganglioma-including patients ≥ 12 years-extending impact to endocrine and pediatric oncology. We provide GU-focused care pathways (operate vs. treat vs. observe), pragmatic placement of belzutifan in RCC lines of therapy, and standardized monitoring for on-target anemia and hypoxia that requires coordinated oncology-hematology-pulmonology management, alongside contraception and drug-interaction counseling. Future priorities include biomarker-guided selection (HIF-2 signatures, EPAS1 variants), optimal sequencing with immunotherapy and VEGF TKIs, evaluation of triplet and peri-operative/adjuvant strategies, and development of next-generation HIF-2 inhibitors to address resistance; exploration of HIF-1 targeting and non-oncology applications (e.g., pulmonary vascular disease) is warranted. Caution is appropriate: overall survival benefit in randomized RCC trials is not yet demonstrated, resistance can emerge, and long-term hematologic and pulmonary effects require surveillance. Together, HIF-2α inhibition establishes a new, clinically actionable axis in GU oncology.

Introduction: In pharmacokinetic (PK) boosting, an intentional drug-drug interaction (DDI) is used to increase the exposure of another drug. PK boosting of the anticancer drug olaparib with the potent Cytochrome P450 (CYP3A)-inhibitor cobicistat can improve oral bioavailability, tolerability, and affordability. Cancer patients often present with many comedications that can also be affected by CYP3A-inhibitors, which requires thorough assessment of DDIs. This may hamper the feasibility of boosting. Here, we report potential DDIs between cobicistat and comedication in a retrospective cohort of patients treated with olaparib and how these DDIs can be mitigated.

Methods: Patients who received olaparib between April 2017 and February 2024 were included. Comedications at the start of olaparib treatment were screened for potential DDIs with cobicistat if PK boosting would have been initiated in these patients. Relevant DDIs were reviewed by an expert panel of pharmacists and clinical pharmacologists and recommendations for mitigating interventions were formulated.

Results: In total, 97 patients were included with a median of six concomitant medications per patient (range 0-13). 59% of patients presented with at least one relevant DDI. With the recommended interventions, 14% of patients had a DDI that required additional monitoring and 1% had a contra-indicated DDI.

Conclusions: DDIs were highly prevalent when PK boosting of olaparib is applied. Nonetheless, nearly all DDIs could be mitigated by an intervention and most interventions could be applied without additional monitoring. PK boosting of olaparib with cobicistat is thus considered feasible with appropriate expertise and resources.