Chemotherapeutic Combinations Research Articles

Optimized low-dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment.

The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late-stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low-dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co-culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell-specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low-dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy.

The efficacy of chemotherapeutic drug combinations may be predicted by concordance of gene response to the single agents.

Determining the expression of genes in response to different classes of chemotherapeutic drugs may allow for a better understanding as to which may be used effectively in combination. In the present study, the human colorectal cancer cell line HCT116 was cultured with equi-active concentrations of a series of anti-cancer agents. Gene expression profiles were then measured by whole-genome microarray. Although each drug induced a unique signature of gene expression in tumour cells, there were marked similarities between certain drugs, even in those from different classes. For example, the antimalarial agent artesunate and the platinum-containing alkylating agent, oxaliplatin, produced a very similar mRNA expression pattern in HCT116 cells with ~14,000 genes being affected by the two drugs in the same way. Furthermore, the overall correlation of gene responses between two agents could predict whether their use in combination would lead to a greater or lesser effect on cell number, determined experimentally, than predicted by single agent experiments. The results indicated that even when working through different mechanisms, combining drugs that initiate a similar transcriptional response may constitute the best option for determining drug-combination strategies for the treatment of cancer.

Cytotoxic and anti-angiogenic effects of zoledronic acid in DU-145 and PC-3 prostate cancer cell lines.

This study aims to investigate the apoptotic and anti-angiogenic effect of Zoledronic acid on hormone-refractory prostate cancer cell lines. XTT cell proliferation assay used to assess cytotoxicity. Caspase 3/7 activity and DNA fragmentation were measured to verify apoptosis. Angiogenic cytokine profiles investigated using the human angiogenesis antibody array I. Administration of Zoledronic acid on PC-3 and DU-145 prostate cancer cell lines resulted in increased cytotoxicity and apoptosis with a time- and dose-related manner. Also, the administration of Zoledronic acid significantly reduced several angiogenic cytokine productions in PC-3 and DU-145 cell lines. Zoledronic acid successfully induced apoptosis and reduced various angiogenic cytokine production in hormone-refractory prostate cancer cell lines. Novel treatment protocols may be developed in the future with chemotherapeutic combinations for the treatment of prostate cancer.

Co-treatment of birinapant with TRAIL synergistically induces apoptosis by downregulating cFLIP(L) in MDA-MB-453 cell lines

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received much attention owing to its ability to specifically induce cell death in cancer. However, several types of cancer, including some forms of breast cancer, are resistant to TRAIL. Various chemotherapeutic agents, phytochemicals, and TRAIL combination therapies have been proposed to resolve TRAIL resistance. Here, we explored the sensitization effect of birinapant on TRAIL-induced apoptosis in the MDA-MB-453 cell line. Although neither birinapant nor TRAIL showed any cytotoxic effect when used alone, apoptosis was induced when birinapant and TRAIL were used together. Our data suggest that the combination of birinapant and TRAIL induces downregulation of FLICE-like inhibitory protein (cFLIP) (L) protein expression. Interestingly, cFLIP(L) overexpression reversed apoptosis caused by co-treatment with TRAIL. Taken together, our results indicate that a combination of birinapant and TRAIL may be a promising treatment for TRAIL-resistant breast cancer.

XRCC1 immunohistochemical expression in DMBA – induced oral squamous cell carcinoma treated with different thymoquinone preparations

The X-ray repair cross-complementing 1 (XRCC1) enzyme plays an important role in the DNA repair pathway. XRCC1 polymorphism increased the risk of human oral squamous cell carcinoma. Loading of thymoquinone on gold nanoparticles as a drug carrier, had revealed a superior anti-cancer effect as a chemotherapeutic agent in DMBA-induced OSCC. This study aimed to evaluate the expression of DNA repair enzyme X-ray repair cross-complementing 1 (XRCC1) following treatment of induced oral cancer in hamster buccal pouch with thymoquinone (TQ) only and loaded on gold nanoparticles (AuNps). Sixty male Syrian golden hamsters were divided into 4 groups: Group A: (negative control). The left pouches of the rest of animals were painted with the carcinogen DMBA (3times / week/ 12 weeks), then: Group B: (positive control), Group C: painted and injected intraperitoneally (i.p) with TQ only (3 times/week for 6 and 12 weeks). Group D: painted with TQ loaded on AuNps (3 times/week for 6 and 12 weeks). After euthanization, all pouches were surgically excised, fixed and processed for H&E and XRCC1 immunohistochemical stains. Groups B, C1, C2, and D1 showed well-differentiated squamous cell carcinoma with low intensity of immune staining. Groups D2 showed remarkable regression of tumors both clinically and histologically with high intensity of IHC staining. Loading of TQ at low concentration (0.001 mg/kg) on AuNps /12 weeks was a promising chemotherapeutic combination, through enhancing XRCC1 expression to regress the carcinogenesis process. This effect could be due to the anti-oxidant, free-radicle scavenging effect and enhancing apoptosis by TQ.

Molecular evaluation of the chemotherapeutic effect of thymoquinone loaded on gold nanoparticles through expression of DNA repair enzymes in induced oral squamous cell carcinoma

Different types of DNA damages occur during the induced oral carcinogenesis, which can be eliminated through several DNA repair pathways. XRCC1 and ERCC1 are the main repair enzymes involved in repair of oral squamous cell carcinoma. A combination of thymoquinone with gold nanoparticles as a novel chemotherapeutic modality is the aim of the present work against chemically induced SCC in the classic model of HBP/DMBA carcinogenesis. One hundred male Syrian golden hamsters were divided into: Group A: Ten animals (negative control), group B: Ten animals (positive control) painted with DMBA only 3times / week/ 12weeks. The rest of animals were painted with DMBA (3times / week/ 12weeks) then painted and injected intraperitoneal with TQ only, 0.01mg/kg TQ-GNps, 0.001mg/kg TQ-GNps or GNps only for 6- and 12- weeks, intervals. By end of the experiment, both pouches from all groups were surgically excised, fresh samples from each pouch were processed for RT-PCR technique. The rest of the pouches were fixed and processed for H&E evaluation. Loading of thymoquinone on gold nanoparticles was promising chemotherapeutic combination, through regression of well-differentiated SCC (positive control) to dysplasia and enhanced expression of the studied DNA repair enzymes compared to either thymoquinone or gold nanoparticles groups.

Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.

Immunoconjugates for Cancer Targeting: A Review of Antibody-Drug Conjugates and Antibody-Functionalized Nanoparticles.

Targeted therapy has been recently highlighted due to the reduction of side effects and improvement in overall efficacy and survival from different types of cancers. Considering the approval of many monoclonal antibodies in the last twenty years, cancer treatment can be accomplished by the combination of monoclonal antibodies and small molecule chemotherapeutics. Thus, strategies to combine both drugs in a single administration system are relevant in the clinic. In this context, two strategies are possible and will be further discussed in this review: antibody-drug conjugates (ADCs) and antibody-functionalized nanoparticles. First, it is important to better understand the possible molecular targets for cancer therapy, addressing different antigens that can selectively bind to antibodies. After selecting the best target, ADCs can be prepared by attaching a cytotoxic drug to an antibody able to target a cancer cell antigen. Briefly, an ADC will be formed by a monoclonal antibody (MAb), a cytotoxic molecule (cytotoxin) and a chemical linker. Usually, surface-exposed lysine or the thiol group of cysteine residues are used as anchor sites for linker-drug molecules. Another strategy that should be considered is antibody-functionalized nanoparticles. Basically, liposomes, polymeric and inorganic nanoparticles can be attached to specific antibodies for targeted therapy. Different conjugation strategies can be used, but nanoparticles coupling between maleimide and thiolated antibodies or activation with the addition of ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) (1:5) and further addition of the antibody are some of the most used strategies. Herein, molecular targets and conjugation strategies will be presented and discussed to better understand the in vitro and in vivo applications presented. Also, the clinical development of ADCs and antibody-conjugated nanoparticles are addressed in the clinical development section. Finally, due to the innovation related to the targeted therapy, it is convenient to analyze the impact on patenting and technology. Information related to the temporal evolution of the number of patents, distribution of patent holders and also the number of patents related to cancer types are presented and discussed. Thus, our aim is to provide an overview of the recent developments in immunoconjugates for cancer targeting and highlight the most important aspects for clinical relevance and innovation.

Ex-vivo drug testing predicts chemosensitivity in acute myeloid leukemia.

The majority of acute myeloid leukemia (AML) patients will respond to standard chemotherapy, however, resistance is a prevalent problem contributing to incomplete responses, refractory disease, and ultimately patient death. Therefore, choosing more sensitive and effective chemotherapy regimens is of key clinical importance. In order to explore this issue, we investigated and optimized PharmaFlow, an automated flow cytometry method for evaluating the sensitivity of leukemia cells to multiple chemotherapeutic drugs ex vivo. We examined bone marrow samples from 38 Chinese AML patients and incubated them for 48 or 72h with a panel of 7 single drugs and 6 combinations with cytarabine at different concentrations. Leukemic cell depletion was assessed by PharmaFlow and drug response parameter, called PharmaFlow score, was estimated using population pharmacodynamic models. We identified that most chemotherapeutic drugs and combinations could effectively eliminate pathological cells ex vivo. Estimated drug activities strongly correlated with the patients' duration to achieve clinical remission and PharmaFlow chemosensitivity measured ex vivo was highly predictive of the clinical outcome after chemotherapy. Applying a classification model, we determined a PharmaFlow score of 89.4 as the threshold to predict response to chemotherapy. Using this threshold, we found that in 84.2% of cases patient's cell response ex vivo predicted the observed clinical response and performed similarly or better than prognostic subgroups determined by cytogenetic characteristics. PharmaFlow has the potential to predict chemosensitivity for de novo, secondary and relapsed AML patients prior to treatment and may guide clinicians to tailor treatments and improve patient outcome.

Optimal Chemotherapeutic Combination of 9 Putative Natural Compounds from Traditional Chinese Medicine

Prostate cancer accounts for 9.9% of all new cancer cases in the United States annually. Despite its high average 5‐year survival rate of 98%, if the cancer metastases to a distant site the 5‐year survival rate drops to just 30.5%. Natural compounds are often studied for their potential chemotherapeutic effects or their sensitizing effects to decrease cancer progression. Traditional Chinese medicine is a common source for finding bioactive small molecules which may have chemotherapeutic effects. This study focused on 9 putative natural compounds and their effectiveness of treating PC‐3 human prostate cancer cells. PC‐3 cancer cells were allowed to adhere for 24h incubated at 37°C with 5% CO2 then treated for 48h. Cell viability was analyzed after an additional 6h incubation with AlamarBlue and tested for relative cell viability. IC50s for each compound were determined and then used in Mixture Design Response Surface Methodology (MDRSM) to determine the optimal mixture of compounds. Chou Talalay statistical analysis was used to determine if combination effects were synergistic, antagonistic or additive. The compounds used include; Triptolide, .01819uM (Ttd), Shikonin, .6002uM (Shk), Curcumin 20.83uM (Cur), Emodin, 57.38uM (Em), Wogonin, 97.87uM (Wo) Berberine, 101.4uM (BB), Silibinin, 106.2uM (or Silybin) (Sy), Epigallocatechin gallate, 272.6uM (EGCG), and β‐Elemene, 304.3uM (β‐E). Emodin, Silibinin and EGCG all appeared to act primarily via cell cycle inhibition and their effectiveness was found to increase in combination with other small molecules. The ideal combination provided a multi‐faced approach reduce cell viability which suggests it may help treat prostate cancer cells in vivo either in tandem with classical chemo‐therapeutics or alone.Support or Funding InformationSimmons Center for Cancer Research

Exosomal Non Coding RNA in LIQUID Biopsies as a Promising Biomarker for Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with a high mortality rate, especially in those that are diagnosed in late stages of the disease. The current screening blood-based markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), have low sensitivity and specificity. Meanwhile, other modalities are either expensive or invasive. Therefore, recent research has shifted towards a minimally invasive test, namely, liquid biopsy. Exosomes are favorable molecules sought in blood samples, since they are abundant, stable in circulation, and harbor genetic information and other biomolecules that could serve as biomarkers or even therapeutic targets. Furthermore, exosomal noncoding RNAs, such as miRNAs, lncRNAs, and circRNAs, have demonstrated the diagnostic potential to detect CRC at an early stage with a higher sensitivity and specificity than CEA and CA19-9 alone. Moreover, they have prognostic potential that is TNM stage specific and could serve as predictive biomarkers for the most common chemotherapeutic drug and combination regimen in CRC, which are 5-FU and FOLFOX, respectively. Therefore, in this review, we focus on the role of these exosomal noncoding RNAs as diagnostic, prognostic, and predictive biomarkers. In addition, we discuss the advantages and challenges of exosomes as a liquid biopsy target.

Simultaneous Optimization of Drug Combination Dose‐Ratio Sequence with Innovative Design and Active Learning

AbstractStrategies for identifying potential drug combinations provide great benefits for the clinical treatment of complex diseases. However, existing approaches primarily focus on optimization of drug combinations and doses without comprehensive joint consideration of drug sequence, which compresses the therapeutic space. Herein, a novel combinatorial drug screening technique is proposed, named innovative design and active learning (IDEAL). This approach integrates innovative design, experimentation, and active learning. IDEAL allows for accurate predictions on the most efficacious drug combination, drug doses, and drug sequence with minimal amount of experimental effort. In this study, IDEAL is applied to lymphoma treatment, which successfully identifies the best drug‐dose sequence combination of chemotherapeutics on Raji cells. The IDEAL optimized regimen indicates that both drug dose and sequence are critical to ensure the optimal phenotype efficacy. This research offers an efficient methodology to identify the optimal drug administration setups in combination therapy.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients With Malignant Ascites Secondary to Unresectable Gastric Cancer.

To compare the efficacy of 3 chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). From January 2010 to December 2013, 38 GC patients were randomly divided into 3 groups and treated by laparoscopic HIPPC with 1 of the 3 following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin (L-OHP), Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the 3 groups. The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months and the median survival was 7.5 months for all patients. Patients in the Ra/L-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/L-OHP group and Ra/MMC group is significantly longer than Ra/DDP group (P<0.05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky performance scale, and incidence rate of port-site metastases among the 3 groups. Laparoscopy-assisted HIPPC provide modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutical combination of Ra/L-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Gamma Tocopherol Reduced Chemotherapeutic-Induced ROS in an Ovarian Granulosa Cell Line, But Not in Breast Cancer Cell Lines In Vitro.

Doxorubicin and cyclophosphamide are used to treat breast cancer, but they also cause infertility through off-target cytotoxicity towards proliferating granulosa cells that surround eggs. Each chemotherapeutic generates reactive oxygen species (ROS) but the effects of the combination, or the antioxidants alpha (αToc) and gamma tocopherol (γToc) on ROS in breast cancer or ovarian cells are unknown. Human breast cancer (MCF7, T47D) and ovarian cancer (OVCAR, COV434) cells were loaded with DCDFA and exposed (1, 2, 3, 24 h) to the MCF7-derived EC25 values of individual agents, or to combinations of these. ROS were quantified and viable cells enumerated using crystal violet or DAPI. Each chemotherapeutic killed ~25% of MCF7, T47D and OVCAR cells, but 57 ± 2% (doxorubicin) and 66 ± 2% (cyclophosphamide) of the COV434 granulosa cells. The combined chemotherapeutics decreased COV434 cell viability to 34 ± 5% of control whereas doxorubicin + cyclophosphamide + γToc reduced ROS within 3 h (p < 0.01) and reduced cytotoxicity to 54 ± 4% (p < 0.05). αToc was not cytotoxic, whereas γToc killed ~25% of the breast cancer but none of the ovarian cells. Adding γToc to the combined chemotherapeutics did not change ROS or cytotoxicity in MCF7, T47D or OVCAR cells. The protection γToc afforded COV434 granulosa cells against chemotherapy-induced ROS and cytotoxicity suggests potential for fertility preservation.

Guar Gum Micro-particles for Targeted Co-delivery of Doxorubicin and Metformin HCL for Improved Specificity and Efficacy Against Colon Cancer: In Vitro and In Vivo Studies.

Doxorubicin and Metformin HCL is a known chemotherapeutic combination that wipes out tumors and prevents their recurrence. However, limited site specificity confines its application. Here we report Doxorubicin and Metformin HCL-loaded guar gum micro-particles prepared by emulsification cum-solidification method. Developed micro-particles were characterized as spherical shape particles with smooth surface and micro size diameter. Encapsulation of drugs in combination was confirmed by their characteristic functional groups (FT-IR), change in phase transition temperature (DSC) and X-ray diffraction pattern (XRD). Particles were observed to be stable at 25 and 5°C. The in vitro Doxorubicin and Metformin HCL release study in simulated gastric (SGF), intestinal (SIF) and colonic fluid (SCF) confirms restricted release in SGF (9.3 and 9.6%, respectively, in 2 h) and SIF (10.8 and 14.7%, respectively, in the next 3 h) and highest release in SCF (about 68 and 73.3%, respectively) in colon. Developed micro-particles showed 78% recovery in tumor volume and considerable improvement in histological changes. X-ray images confirmed good target ability of micro-particles to colon. In conclusion, the specially designed, stable micro-particles are able to target drug combination to colon and improve efficacy by ensuring maximum drug release in colon as compared with Doxorubicin and Metformin HCL combination.

Synergistic Effect of 1,3,6-Trihydroxy-4,5,7-Trichloroxanthone in Combination with Doxorubicin on B-Cell Lymphoma Cells and Its Mechanism of Action Through Molecular Docking

The increasing rate of cancer chemoresistance and adverse side effects of therapy have led to the wide use of various chemotherapeutic combinations in cancer management, including lymphoid malignancy. We investigated the effects of a combination of 1,3,6-trihydroxy-4,5,7-trichloroxanthone (TTX) and doxorubicin on the Raji lymphoma cell line. Raji cells were treated with different concentrations of TTX, doxorubicin, or combinations thereof. Cancer cell growth inhibition was evaluated using 3-(4,5-dimethyltiazol-2-yl)-2,5- diphenyltetrazolium bromide/MTT assay to determine the half-maximal inhibitory concentration. Combination index values were calculated using CompuSyn (ComboSyn, Inc, Paramus, NJ). Molecular docking was conducted using a Protein-Ligand ANT System. The mean (SD) half-maximal inhibitory concentration values of TTX and doxorubicin were 15.948 (3.101) µM and 25.432 (1.417) µM, respectively. The combination index values of the different combinations ranged from 0.057 to 0.285, indicating strong to very strong synergistic effects. The docking study results reveal that TTX docks at the active site of Raf-1 and c-Jun N-kinase receptors with predicted free energies of binding of -79.37 and -75.42 kcal/mol, respectively. The xanthone-doxorubicin combination showed promising in vitro activity against lymphoma cells. The results also indicate that the TTX and doxorubicin combination's effect was due to the interaction between TTX with Raf-1 and c-Jun N-kinase receptors, 2 determinants of doxorubicin resistance progression.

Enhancing doxorubicin anticancer activity with a novel polymeric platform photoreleasing nitric oxide.

Combinations of conventional chemotherapeutics with unconventional anticancer agents such as reactive oxygen and nitrogen species may offer treatment benefits for cancer therapies. Here we report a novel polymeric platform combining the delivery of Doxorubicin (DOXO) with the light-regulated release of nitric oxide (NO). An amphiphilic block-copolymer (P1) was designed and synthesized as the drug carrier, with pendant amine groups to attach DOXO via a urea linkage and a NO photodonor (NOPD) activable by visible light. The two grafted-copolymers (P1-DOXO and P1-NOPD) self-assembled via solvent displacement methods into nanoparticles (NPs), containing both therapeutic components (NP1) and, for comparison, the individual NOPD (NP2) and DOXO (NP3). All the NPs were fully characterized in terms of physicochemical, photochemical and photophysical properties. These experiments demonstrated that integration of the NOPD within the polymeric scaffold enhanced the NO photoreleasing efficiency when compared with the free NOPD, and that the proximity to DOXO on the polymer chains did not significantly affect the enhanced photochemical performance. Internalization of the NPs into lung, intestine, and skin cancer cell lines was investigated after co-formulation with Cy5 fluorescent tagged polymers, and cytotoxicity of the NPs against the same panel of cell lines was assessed under dark and light conditions. The overall results demonstrate effective cell internalization of the NPs and a notable enhancement in killing activity of the dual-action therapeutic NP1 when compared with NP2, NP3 and the free DOXO, respectively. This suggests that the combination of DOXO with photoregulated NO release, achieved through the mixed formulation strategy of tailored polymer conjugate NPs, may open new treatment modalities based on the use of NO to improve cancer therapies.

Modified gaphene oxide (GO) particles in peptide hydrogels: a hybrid system enabling scheduled delivery of synergistic combinations of chemotherapeutics.

The scheduled delivery of synergistic drug combinations is increasingly recognized as highly effective against advanced solid tumors. Of particular interest are composite systems that release a sequence of drugs with defined kinetics and molar ratios to enhance therapeutic effect, while minimizing the dose to patients. In this work, we developed a homogeneous composite comprising modified graphene oxide (GO) nanoparticles embedded in a Max8 peptide hydrogel, which provides controlled kinetics and molar ratios of release of doxorubicin (DOX) and gemcitabine (GEM). First, modified GO nanoparticles (tGO) were designed to afford high DOX loading and sustained release (18.9% over 72 h and 31.4% over 4 weeks). Molecular dynamics simulations were utilized to model the mechanism of DOX loading as a function of surface modification. In parallel, a Max8 hydrogel was developed to release GEM with faster kinetics and achieve a 10-fold molar ratio to DOX. The selected DOX/tGO nanoparticles were suspended in a GEM/Max8 hydrogel matrix, and the resulting composite was tested against a triple negative breast cancer cell line, MDA-MB-231. Notably, the composite formulation afforded a combination index of 0.093 ± 0.001, indicating a much stronger synergism compared to the DOX-GEM combination co-administered in solution (CI = 0.396 ± 0.034).

18F-fluorodeoxyglucose positron emission tomography-computed tomography in response assessment of perivascular epithelioid cell tumor of the pelvic cavity to irinotecan and temozolomide

Perivascular epithelioid cell tumors (PEComas) are a rare variety of mesenchymal tumors composed of distinctive cells that show a focal association with blood vessel walls and usually express melanocytic and smooth muscle markers. We present a case of 38-year-old male, diagnosed with PEComa of the pelvic cavity who underwent serial 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans for the assessment of response to the chemotherapeutic combination of irinotecan and temozolomide.

Changing paradigm of radiation therapy for the treatment of pancreatic cancer

AbstractThe evidence supporting the use of radiation therapy (RT) for pancreatic cancer (PC) treatment is highly variable, with studies both showing and failing to show that RT provides a survival benefit. Trials exploring the use of RT for PC treatment dates back to the 1960s with various dosing and fractionation schemes, as well as various chemotherapeutic combinations. Collectively, large retrospective studies using cancer databases have shown an overall survival benefit with the addition of RT. The combination of RT with efficacious chemotherapy regimens synergistically improves the benefits of RT. More recent studies have evaluated the use of stereotactic body radiation therapy in either single‐ or multi‐fraction regimens. Modern studies using multifractionated stereotactic body radiation therapy have demonstrated maintenance of local control and safe toxicity profiles with shorter therapeutic regimens allowing for improved integration with other therapeutic modalities. Although the use of RT has been evaluated for ≥50 years for PC treatment, the heterogeneous nature of the studies carried out and the advancement of complementary chemotherapeutic regimens makes it difficult to clearly identify the direct effect of RT. Herein, we provide a comprehensive overview of the evidence for the use of RT in PC treatment, including a comparison of conventionally fractionated RT versus stereotactic body radiation therapy.