Cancer Chemotherapy Agents Research Articles

Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Liver Failure After Resection of Colorectal Liver Metastases.

Chemotherapy agents for metastatic colorectal cancer can cause liver injury, increasing the risk of post-hepatectomy liver failure after hepatectomy for metastases. The role of noninvasive fibrosis markers in this setting is not well established. To evaluate the aspartate aminotransferase-to-platelet ratio index (APRI) as a predictor of postoperative liver failure. The National Surgical Quality Improvement Program database was utilized to identify patients who received preoperative chemotherapy and underwent hepatectomy for colorectal metastases between 2015 and 2017. Concordance index analysis was conducted to determine APRI's contribution to the prediction of liver failure. The optimal cutoff value was defined and its ability to predict post-hepatectomy liver failure and perioperative bleeding were examined. A total of 2374 patients were identified and included in the analysis. APRI demonstrated to be a better predictor of postoperative liver failure than MELD score, with a statistically significant larger area under the curve. The optimal APRI cutoff value to predict liver failure was 0.365. The multivariable logistic regression showed that APRI ≥ 0.365 was independently associated with PHLF, odds ratio (OR) 2.51, 95% confidence interval (CI) 1.67-3.77, P < .0001. Likewise, APRI ≥ 0.365 was independently associated with perioperative bleeding complications requiring transfusions, OR 1.41, 95% CI 1.13-1.77, P = 0.002. MELD score was not statistically associated with PHLF or bleeding complications. APRI was independently associated with post-hepatectomy liver failure and perioperative bleeding requiring transfusions after resection of colorectal metastases in patients who received preoperative chemotherapy. Concordance index showed APRI to add significant contribution as a predictor of postoperative liver failure.

Plant asparaginase versus microbial asparaginase as anticancer agent.

The considerable effect of enzymes on human health draws great attention to enzyme-based drugs (therapeutic enzymes), in recent times. L-asparaginase (ASNase) is a well-known therapeutic enzyme. It has varied applications and is a single molecule for the treatment of multiple diseases. This study tries to extract asparaginase from soybean debris (agricultural wastes) as a cheap plant source and compare this with microbial asparaginase as an agent in cancer chemotherapy. The asparaginase was extracted and purified from soybean debris (plant asparaginase) and Pseudomonas aeruginosa (microbial asparaginase), then the physiochemical characters were determined for the two enzymes, and the anticancer activity of plant and microbial asparaginase was determined against gastric cancer (CLS-145), pancreatic cancer (AsPC-1), colon cancer (HCT116), esophagus cancer (KYSE-410), liver cancer (HepG2), breast cancer (MCF-7), and cervical cancer (HELLA). The results showed that plant asparaginase was superior to microbial asparaginase in its physiochemical characters. Plant asparaginase showed higher stability and activity under the conditions of changing either the temperature or the pH; also plant asparaginase has a higher affinity to the asparagine than the microbial asparaginase; besides, this plant asparaginase did not show activity with glutamine as a substrate. The plant asparaginase showed higher anticancer activity than that of microbial asparaginase against all studied cancer cell lines. The present study introduces as the first time a comparative study between the plant and microbial asparaginase which proves that soybean debris asparaginase can be more efficient and safe than that of the microbial asparaginase as an anticancer agent.

Exonuclease 1 genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

Pemetrexed is an anti-folate agent which is one of the most frequently used chemotherapy agents for non-squamous non-small cell lung cancer (NSCLC) patients. However, clinical response to pemetrexed chemotherapy and survival outcome of patients varies significantly. We evaluated whether the genetic variants in miRNA target sites may affect the treatment outcome of pemetrexed chemotherapy in lung adenocarcinoma patients. One hundred SNPs in miRNA binding regions in cancer-related genes were obtained from the crosslinking, ligation, and sequencing of hybrids (CLASH) and CancerGenes database, and the associations with the response to pemetrexed chemotherapy and survival outcomes were investigated in 314 lung adenocarcinoma patients. Two polymorphisms, EXO1 rs1047840G>A and CAMKK2 rs1653586G>T, were significantly associated with worse chemotherapy response (adjusted odds ratio [aOR] = 0.41, 95% CI = 0.24-0.68, P = 0.001, under dominant model; and aOR = 0.33, 95% CI = 0.16-0.67, P = 0.002, under dominant model, respectively) and worse OS (adjusted hazard ratio [aHR] = 1.34, 95% CI = 1.01-1.77, P = 0.04, under dominant model; and aHR = 1.50, 95% CI = 1.06-2.13, P = 0.02, under dominant model, respectively) in multivariate analyses. Significantly increased luciferase activity was noted in EXO1 rs1047840 A allele compared to G allele. In conclusion, two SNPs in miRNA binding sites, especially EXO1 rs1047840G>A, were associated with the chemotherapy response and survival outcome in lung adenocarcinoma patients treated with pemetrexed.

&amp;lt;i&amp;gt;Desmarestia anceps&amp;lt;/i&amp;gt; Montagne (Phaeophyceae) against Colorectal Cancer Cells: Cytotoxic Activity and Proapoptotic Effects

Impairment of apoptosis promotes abnormal cellular proliferation and accumulation of genetic alterations. Identifying bioactive compounds extracted from seaweeds that induce apoptosis in cancer cells may be explored as new agents for cancer chemoprevention and/or chemotherapy. The present study aimed to determine the chemical composition and biological activity of the chloroform crude extract and fractions from Antarctic seaweed Desmarestia anceps. The chloroform extract was obtained by three consecutive macerations and the fractionation by vacuum liquid chromatography. The chemical characterization of the extract and fractions was performed through Gas Chromatography. The cytotoxicity of the crude extract and fractions was evaluated by the MTT assay. Cell death and cell cycle evaluation after 24 hours of exposure to chloroform extract were performed by flow cytometry. A total of 48 compounds were identified. The results indicate that chloroform extract and its fractions presented cytotoxic activity against HCT 116 cell line in a dose dependent-manner. Proapoptotic events were observed after chloroform extract exposition, which promoted an increase of multinucleated cells and reduced cell viability. This study was the first to explore cytotoxic potential of seaweed D. anceps fractions against HCT colorectal cancer cell line, suggesting that these macroalgae may be a promising candidate against anticancer activity.

Ring A/B-Modified 17β-Hydroxywithanolide Analogues as Antiproliferative Agents for Prostate Cancer and Potentiators of Immunotherapy for Renal Carcinoma and Melanoma.

Physachenolide C (1) is a 17β-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 μM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17β-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.

FOLFIRINOX Not Better Than Gemcitabine-Cisplatin in Biliary Cancer

Standard chemotherapy agents for advanced biliary cancer are gemcitabine and cisplatin. Recent data suggest a modest benefit for use of second-line

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells.

Simple SummaryThe dysfunction of microtubule nucleation in cancer cells changes the overall cytoskeleton organization and cellular physiology. This review focuses on the dysregulation of the γ-tubulin ring complex (γ-TuRC) proteins that are essential for microtubule nucleation. Recent research on the high-resolution structure of γ-TuRC has brought new insight into the microtubule nucleation mechanism. We discuss the effect of γ-TuRC protein overexpression on cancer cell behavior and new drugs directed to γ-tubulin that may offer a viable alternative to microtubule-targeting agents currently used in cancer chemotherapy.In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy.

Synthesis and biological evaluation of chalcone-polyamine conjugates as novel vectorized agents in colorectal and prostate cancer chemotherapy.

The aim of this study was to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. Indeed, it is well-known that polyamine transport system is upregulated in tumor cells. 3',4,4',5'-tetramethoxychalcone was selected as parent chalcone since it was found to be an efficient anti-proliferative agent on various cancer cells. A series of five chalcone-polyamine conjugates was obtained using the 4-bromopropyloxy-3',4',5'-trimethoxychalcone as a key intermediate. Chalcone core and polyamine tails were fused through an amine bond. These conjugates were found to possess a marked invitro antiproliferative effect against colorectal (HT-29 and HCT-116) and prostate cancer (PC-3 and DU-145) cell lines. The most active conjugate (compound 8b) was then chosen for further biological evaluations to elucidate mechanisms responsible for its antiproliferative activity. Investigations on cell cycle distribution revealed that this conjugate can prevent the proliferation of human colorectal and prostate cancer cells by blocking the cell cycle at the G1 and G2 phase, respectively. Flow cytometry analysis revealed a sub-G1 peak, characteristic of apoptotic cell population and our inquiries highlighted apoptosis induction at early and later stages through several pro-apoptotic markers. Therefore, this chalcone-N1-spermidine conjugate could be considered as a promising agent for colon and prostatic cancer adjuvant therapy.

Dorsal root ganglion toll-like receptor 4 signaling contributes to oxaliplatin-induced peripheral neuropathy.

Activation of toll-like receptor 4 (TLR4) in the dorsal root ganglion (DRG) and spinal cord contributes to the generation of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Generalizability of TLR4 signaling in oxaliplatin-induced CIPN was tested here. Mechanical hypersensitivity developed in male SD rats by day 1 after oxaliplatin treatment, reached maximum intensity by day 14, and persisted through day 35. Western blot revealed an increase in TLR4 expression in the DRG of oxaliplatin at days 1 and 7 after oxaliplatin treatment. Cotreatment of rats with the TLR4 antagonist lipopolysaccharide derived from Rhodobacter sphaeroides ultrapure or with the nonspecific immunosuppressive minocycline with oxaliplatin resulted in significantly attenuated hyperalgesia on day 7 and 14 compared with rats that received oxaliplatin plus saline vehicle. Immunostaining of DRGs revealed an increase in the number of neurons expressing TLR4, its canonical downstream signal molecules myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β, at both day 7 and day 14 after oxaliplatin treatment. These increases were blocked by cotreatment with either lipopolysaccharide derived from Rhodobacter sphaeroides or minocycline. Double staining showed the localization of TLR4, MyD88, and TIR-domain-containing adapter-inducing interferon-β in subsets of DRG neurons. Finally, there was no significant difference in oxaliplatin-induced mechanical hypersensitivity between male and female rats when observed for 2 weeks. Furthermore, upregulation of TLR4 was detected in both sexes when tested 14 days after treatment with oxaliplatin. These findings suggest that the activation of TLR4 signaling in DRG neurons is a common mechanism in CIPN induced by multiple cancer chemotherapy agents.

Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα.

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood-brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain's antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFΑ are involved in chemotherapy-induced cognitive impairment.

Efficacy and safety of 5\u2009mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials

BackgroundThe efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine’s efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine.MethodsData were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors.ResultsRegarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist.ConclusionsThe findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

Shengbai decoction enhances the anti-tumor efficacy of cyclophosphamide on hepatoma 22-bearing mice

Combination therapies with chemotherapy and traditional Chinese medicines are attracted increasing attentions for cancer treatment in China. Shengbai decoction (SBD) is a traditional Chinese compound medicine, composed of 6 traditional Chinese herbs. The aim of this study was to investigate the synergistic anti-tumor activity of SBD with cyclophosphamide (CTX) and the possibly underlying mechanisms in treating the hepatoma 22 (H22) -bearing mice. The liver cancer models in C57BL/6 mice were established by injecting with mouse H22 cancer cells. Results showed that combination treatment with SBD and CTX processed a significantly synergistic anti-tumor effect in H22 tumor-bearing mice. Moreover, SBD could not only improve leukopenia caused by CTX, but prolong the survival time of the mice. Furthermore, SBD could upregulate the expressions of the pro-apoptotic genes, including p53, BAD, Cas3 and Bax, and suppress the expression of anti-apoptotic gene Bcl-2. These results suggested that the combination treatment with SBD and CTX had health improving function and less side effects compared with the administration of CTX alone, and SBD could be a promising adjunct agent for liver cancer chemotherapy.

Doxorubicin Cytotoxicity and Mitochondrial Changes in Human Proximal Tubular Epithelial Cells (HK‐2) is Partially Prevented by Resveratrol

The cancer chemotherapy agent Doxorubicin (DOX, Adriamycin), is FDA approved for use in the treatment regimen for acute lymphoid leukemia, breast, Hodgkin and Non-Hodgkin lymphomas, small cell lung cancer and advanced non-small cell lung cancer. Serious adverse effects include cardiomyopathy, congestive heart failure and renal dysfunction. The cellular mechanisms for doxorubicin mediated renal cytotoxicity have not been entirely identified. The trans-stilbene resveratrol (RES) is a phytoalexin found in Japanese knotweed, grape skins, blueberries, cranberries, dark chocolate and nuts. Antioxidant and anticancer properties have been associated with RES in cell culture and in human clinical studies. Our studies examined RES protection for DOX renal cytotoxicity by maintaining mitochondrial function. All studies were conducted in human noncancerous renal proximal tubular epithelial cells (HK-2). HK-2 cells were plated and equilibrated for 48 h. Cells were next pre-incubated for 1 h with 0 (DMSO) or up to 10 uM RES followed by a 24 h co-incubation with 0-5 uM DOX. All results were obtained from 3 independent experiments. Western analysis probed for protein carbonylation was used as an indicator of oxidative stress. Mitochondrial function was assessed using a Seahorse analyzer system. Prior to examining mitochondrial function, cell number and substrate concentrations were optimized. Mitochondrial Stress Test was conducted following the treatments described above and each well was normalized by protein. Viability was assessed using MTT leakage and trypan blue exclusion cell counts. RES did not alter cell viability as indicated by comparable MTT values between DMSO and RES groups (p>0.05). DOX was cytotoxic to HK-2 cells within 24 h. Pretreatment with RES provided protection from DOX to HK-2 cells. Basal mitochondrial respiration assessed as oxygen consumption rate (OCR) was diminished by 4 uM DOX. Mitophagy was probed using protein expression of LC3BI, LC3BII and the ratio of LC3BII/I following DOX exposure. In summary, RES attenuated DOX renal cytotoxicity by maintaining mitochondrial OCR near normal.

An Amphiphilic PEGylated Peptide Dendron-Gemcitabine Prodrug-Based Nanoagent for Cancer Therapy.

An amphiphilic peptide dendrimer conjugated with gemcitabine (GEM), PEGylated dendron-Gly-Phe-Leu-Gly-GEM (PEGylated dendron-GFLG-GEM), is developed as a nano-prodrug for breast cancer therapy. The self-assembled behavior is observed under a transmission electron microscopy and dynamic light scattering. The negatively charged surface and hydrodynamic size of the amphiphilic nanosized prodrug supported that the prodrug can maintain the stability of GEM during circulation and accumulate in the tumor tissue. Drug release assays are conducted to monitor the release of GEM from this nanodrug delivery system in response to the tumor microenvironment, and these assays confirm that GEM released from the nanocarrier is identical to free GEM. The GEM prodrug can prevent proliferation of tumor cells. The therapeutic effect against breast cancer is systematically investigated using an in vivo animal model. Immunohistochemical results are aligned with the significantly enhanced anticancer efficacy of GEM released from the prodrug. This self-assembled amphiphilic drug delivery nanocarrier may broaden the application for GEM and other anticancer agents for breast cancer chemotherapy.

Gastrointestinal and liver adverse effects of anti-tumoral immune therapy: from recognition to treatment.

Anti-tumoral immune therapy consists of monoclonal antibodies that target intra-cellular immune checkpoints—which under normal circumstances, act as regulators of T-cell immunity. By serving as inhibitors of cellular checkpoints, monoclonal antibodies stimulate the immune system thus augmenting the body’s response against cancer. These immune-enhancers or stimulators have revolutionized the treatment of malignancy as they continue to show improvement in the overall survival of cancer patients. Currently, in the United States, six immune checkpoint inhibitors are approved for the treatment of a variety of solid tumors (1). As these checkpoint inhibitors are relatively new, only a scant amount of literature is available regarding both their adverse effects and management thereof. In addition, as newer antibodies are being developed, and expected to be enlisted among the armamentarium of cancer chemotherapeutic agents—the need to understand their toxicity and adverse effects is of paramount importance. Herein, we review some of the gastrointestinal and liver sequelea secondary to the usage of immunotherapeutic checkpoint inhibitor agents in cancer chemotherapy, as well as present the diagnosis and recommended treatment strategies for their adverse effects. Keywords: Anti-tumoral immune therapy, Treatment, Gastrointestinal and liver diseases. (Please cite as: Weissman S, Saleem S, Al-Dulaimi D. Gastrointestinal and Liver adverse effects of anti-tumoral immune therapy: from recognition to treatment. Gastroenterol Hepatol Bed Bench 2021;14(3):195-199).

Challenges and Opportunities to Develop Enediyne Natural Products as Payloads for Antibody-Drug Conjugates.

Calicheamicin, the payload of the antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg®) and inotuzumab ozogamicin (Besponsa®), belongs to the class of enediyne natural products. Since the isolation and structural determination of the neocarzinostatin chromophore in 1985, the enediynes have attracted considerable attention for their value as DNA damaging agents in cancer chemotherapy. Due to their non-discriminatory cytotoxicity towards both cancer and healthy cells, the clinical utilization of enediyne natural products relies on conjugation to an appropriate delivery system, such as an antibody. Here, we review the current landscape of enediynes as payloads of first-generation and next-generation ADCs.

Zingiber Officinale Var. Rubrum Extract Increases The Cytotoxic Activity Of 5-Fluorouracil In Colon Adenocarcinoma Widr Cells

One of the main chemotherapy agents for colon cancer is 5-fluorouracil (5-FU). However, the effectiveness of 5-FU decreased; therefore, co-chemotherapy with another agent is needed to enhance the activity. This study aims to determine the effect of red ginger extract as a co-chemotherapy agent with 5-FU on WiDr colon adenocarcinoma cells. We investigated the cytotoxic activity of the ethanolic extract of rhizome red ginger and combination with 5-fluorouracil (5-FU) in WiDr human colorectal cancer cell line. Red ginger extract was extracted by using 96% ethanol. Cytotoxic assay of red ginger extract and 5-FU was performed using MTT assay for 24 and 48 hours. Treatment of 5-FU in WiDr cells for 48 hours showed an IC50 value of 130 µg/mL, while no IC50 value was obtained for the 24 hours treatment. Treatment of red ginger extract with an incubation time of 24 and 48 hours had a cytotoxic effect on WiDr cells with IC50 values of 68 µg/mL and 65 µg/mL, respectively. The combination of 1000 μg/mL 5-fluorouracil with 35 μg/mL red ginger extract at 24-hour incubation resulted in a smaller cell viability value than every single treatment. The combination treatment of 5-FU 60 μg/mL with red ginger extract at a 25 μg/mL concentration causes a more significant decrease in cell viability than a single 5-FU treatment. In conclusion, red ginger extract may increase the cytotoxic activity of 5-FU in colon adenocarcinoma WiDr cells.

Pattern of adverse drug reactions in rural tertiary care medical college and hospital of Himachal Pradesh: A retrospective observational study

Introduction: Adverse events can lead to admission in hospital, prolongation of hospitalization, increase in investigations as well as treatment costs, deformities, danger to life and even death. Objective: The aim of this study was to conduct adverse drug reactions (ADRs) monitoring in various departments of a tertiary care teaching hospital. Methods: A retrospective observational study was conducted on ADRs reported in adverse drug monitoring center of our hospital from April, 2016 to December, 2016. Data such as age, gender, diagnosis, drug intake, types of ADRs, treatment and outcome of the reactions were collected. Each reported patient was assessed individually. Causality assessment was done on Naranjo’s probability scale. Modified Hartwig’s criteria were used to assess the severity of ADRs. Results: A total of 173reports were studied. 65(38%) patients were males and 108 (62%) were females. The majority of ADRs were due to cancer chemotherapy agents in 87(50%), followed by anti-tubercular drugs in 22(13%), antimicrobial agents in 22 (13%) and anti-retroviral drugs in 16(9%).Out of total 574 events 192(34%)complaints comprised of gastro-intestinal manifestations. On Naranjo’s probability scale, 111(64%) reactions were probable, 54 (31%) as possible and 8 (5%) as certain. According to Modified Hartwig’s criteria 130 (75%) reactions were mild, 29 (17%) were moderate and 14(8%) were severe. Conclusion: Health-care providers will have to do vigilant monitoring and reporting of ADR´s. Keywords: Pharmacovigilance, Adverse drug reactions, Chemotherapy, Causality assessment, Tertiary care teaching hospital.

Molecular genomic features associated with invitro response of the NCI-60 cancer cell line panel to natural products.

Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with invitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.

The Bromodomain Inhibitor PFI-3 Sensitizes Cancer Cells to DNA Damage by Targeting SWI/SNF.

Many chemotherapeutic drugs produce double-strand breaks (DSB) on cancer cell DNA, thereby inducing cell death. However, the DNA damage response (DDR) enables cancer cells to overcome DNA damage and escape cell death, often leading to therapeutic resistance and unsuccessful outcomes. It is therefore important to develop inhibitors that target DDR proteins to render cancer cells hypersensitive to DNA damage. Here, we investigated the applicability of PFI-3, a recently developed bromodomain inhibitor specifically targeting the SWI/SNF chromatin remodeler that functions to promote DSB repair, in cancer treatment. We verified that PFI-3 effectively blocks chromatin binding of its target bromodomains and dissociates the corresponding SWI/SNF proteins from chromatin. We then found that, while having little toxicity as a single agent, PFI-3 synergistically sensitizes several human cancer cell lines to DNA damage induced by chemotherapeutic drugs such as doxorubicin. This PFI-3 activity occurs only for the cancer cells that require SWI/SNF for DNA repair. Our mechanism studies show that PFI-3 exerts the DNA damage-sensitizing effect by directly blocking SWI/SNF's chromatin binding, which leads to defects in DSB repair and aberrations in damage checkpoints, eventually resulting in increase of cell death primarily via necrosis and senescence. This work therefore demonstrates the activity of PFI-3 to sensitize cancer cells to DNA damage and its mechanism of action via SWI/SNF targeting, providing an experimental rationale for developing PFI-3 as a sensitizing agent in cancer chemotherapy. IMPLICATIONS: This study, revealing the activity of PFI-3 to sensitize cancer cells to chemotherapeutic drugs, provides an experimental rationale for developing this bromodomain inhibitor as a sensitizing agent in cancer chemotherapy.