Side Effects Of Anticancer Agents Research Articles

Chrysin protects against kidney tissue damage caused by pemetrexed used in cancer treatment

Pemetrexed (PMTX) is a multi-targeted, anticancer, antifolate agent that exerts its effect by disrupting the folate-dependent metabolic processes underlying cell proliferation. Kidney toxicity is a common side effect of anticancer agents. Chrysin (Chr) is a powerful antioxidant compound abundant in plant extracts, honey, and bee propolis. The aim of this study is to investigate the effect of the combined use of chrysin, a natural flavonoid, against the possible harmful effects of PMTX on kidney tissue. 50 male Wistar albino rats were divided into five groups: Control, Sham, PMTX, Chr, PMTX+Chr. Sham (1ml corn oil/day), CH (50mg/kg/day) by oral gavage, PMTX (1mg/kg/week) by i.p., PMTX+CH (PMTX;1mg/kg/week, CH;50mg/kg/day) were given at the same time every day. At the end of 4 weeks at the end of the study, blood and kidney tissues were collected. The malondialdehyde (MDA), superoxide dismutase (SOD) activities, and total antioxidant (TAS), total oxidant status (TOS), OSI also were measured. Blood-urea-nitrogen (BUN) and creatinine (Cr) analyzed by ELISA. Indicators of oxidative stress, MDA was elevated and antioxidant activity was reduced in the PMTX group compared to control and Sham (p <0,05). In the PMTX+Chr group, MDA, BUN, Cr and TOS were decreased, SOD and TAS was increased compared to PMTX group (p <0,05). We found that Chr exhibited ameliorative effects on PMTX induced nephrotoxicity increasing antioxidant activity and reducing oxidative damage.

Polymeric Nanoparticles—Tools in a Drug Delivery System in Selected Cancer Therapies

The increase in cancer cases is undoubtedly affecting the development of new therapeutic approaches. Polymeric nanoparticles are of great interest. Due to their relatively small size, the possibility of incorporating into them medicinal substances and the ease with which their physicochemical properties may be manipulated, they are being used as anticancer drug delivery systems. The aim of this review is to focus on the use of nanoscale polymeric particles in the treatment of colorectal cancer, breast cancer, ovarian cancer and glioblastoma multiforme, and to consider their potential use in cancer gene therapy. According to several reports, the use of polymer nanoparticles as drug carriers is promising in solid tumors. With their application, it is possible to precisely deliver medicinal substances to the tumor structure, to overcome the blood–brain barrier in the case of brain tumors, to reduce the side effects of anticancer agents on normal cells and to achieve a therapeutic effect with a lower drug dose. Additionally, a number of reports indicate that they can also be used in combination with other methods of cancer treatment, mainly radiotherapy.

Antiproliferative and Apoptotic Effects of Graphene Oxide @AlFu MOF Based Saponin Natural Product on OSCC Line.

The increasing rate of oral squamous cell carcinoma (OSCC) and the undesirable side effects of anticancer agents have enhanced the demand for the development of efficient, detectable, and targeted anticancer systems. Saponins are a diverse family of natural glycosides that have recently been evaluated as an effective compound for the targeted therapy of squamous cell carcinoma. Due to their porous nature and stable structure, metal–organic frameworks (MOFs) are a well-known substance form for various biological applications, such as drug delivery. In this study, we fabricated a novel hybrid, highly porous and low-toxic saponin-loaded nanostructure by modifying graphene oxide (GO)/reduced GO (rGO) with aluminum fumarate (AlFu) as MOF core–shell nanocomposite. The characterization of the nanostructures was investigated by FTIR, TEM, EDX, FESEM, and BET. MTT assay was used to investigate the anticancer activity of these compounds on OSCC and PDL normal dental cells. The effect of the nanocomposites on OSCC was then investigated by studying apoptosis and necrosis using flow cytometry. The GO/rGO was decorated with a saponin–AlFu mixture to further investigate cytotoxicity. The results of the MTT assay showed that PDL cells treated with AlFu–GO–saponin at a concentration of 250 μg/mL had a viability of 74.46 ± 16.02%, while OSCC cells treated with this sample at a similar concentration had a viability of only 38.35 ± 19.9%. The anticancer effect of this nanostructure on OSCC was clearly demonstrated. Moreover, the number of apoptotic cells in the AlFu–GO–saponin and AlFu–rGO–saponin groups was 10.98 ± 2.36%–26.90 ± 3.24% and 15.9 ± 4.08%–29.88 ± 0.41%, respectively, compared with 2.52 ± 0.78%–1.31 ± 0.62% in the untreated group. This significant increase in apoptotic effect observed with AlFu–rGO–saponin was also reflected in the significant anticancer effect of saponin-loaded nanostructures. Therefore, this study suggests that an effective saponin delivery system protocol for the precise design and fabrication of anticancer nanostructures for OSCC therapy should be performed prior to in vivo evaluations.

Lapatinib-loaded acidity-triggered charge switchable polycarbonate-doxorubicin conjugate micelles for synergistic breast cancer chemotherapy

Stimulus-responsive nanosystem is a powerful method to improve the bioavailability and reduce the side effects of anticancer agents. In the present study, a customized dual pH-responsive micellar nanoplatform (DOX+LAP-M) based on polycarbonate-doxorubicin conjugate micelles was prepared to co-deliver the chemotherapeutic agent lapatinib for inhibiting tumor growth and metastasis. DOX+LAP-M micelles with spherical morphology had a size of ~112 nm and had an initial negative surface charge, which are favorable characteristics for long-term circulation in the blood. Once the micelles accumulated in tumor tissues, the intrinsic tumor extracellular acidity triggered the charge switch of DOX+LAP-M micelles from -1 to 9 mV, thereby facilitating cell internalization and tumor penetration. Subsequently, the pH-sensitive micellar core accelerated the release of doxorubicin and lapatinib in the acidic intracellular environment. DOX+LAP-M micelles effectively inhibited the proliferation, migration, and invasion of 4T1 cells in vitro; furthermore, the administration of DOX+LAP-M micelles in 4T1 xenograft-bearing mice suppressed solid tumor growth with an inhibitory rate of 90.2% and significantly decreased pulmonary metastatic nodules, without significant systemic toxicity. This multifunctional micellar system has high potential for clinical cancer therapy.

Anti-Cancer Activity of a 5-Aminopyrazole Derivative Lead Compound (BC-7) and Potential Synergistic Cytotoxicity with Cisplatin against Human Cervical Cancer Cells.

The use of some very well-known chemotherapeutic agents, such as cisplatin, is limited by toxicity in normal tissues and the development of drug resistance. In order to address drug resistance and the side-effects of anti-cancer agents, recent research has focused on finding novel combinations of anti-cancer agents with non-overlapping mechanisms of action. The cytotoxic effect of the synthetic 5-aminopyrazole derivative N-[[3-(4-bromophenyl)-1H-pyrazol-5-yl]-carbamothioyl]-4-chloro-benzamide (BC-7) was evaluated by the bis-Benzamide H 33342 trihydrochloride/propidium iodide (Hoechst 33342/PI) dual staining method against HeLa, MeWo, HepG2, Vero, and MRHF cell lines. Quantitative fluorescence image analysis was used for the elucidation of mechanism of action and synergism with cisplatin in HeLa cells. BC-7 displayed selective cytotoxicity towards HeLa cells (IC50 65.58 ± 8.40 μM) and induced apoptosis in a mitochondrial- and caspase dependent manner. This was most likely preceded by cell cycle arrest in the early M phase and the onset of mitotic catastrophe. BC-7 increased the cytotoxic effect of cisplatin in a synergistic manner with combination index (CI) values less than 0.9 accompanied by highly favourable dose reduction indices. Therefore, the results obtained support the implication that BC-7 has potential anti-cancer properties and that combinations of BC-7 with cisplatin should be further investigated for potential clinical applications.

Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool.

Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient’s quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.

Transport Phenomenon of Nanoparticles in Animals and Humans

Nanoparticles (NPs) are microscopic objects with at least one dimension less than 100 nm. These were first discovered by Michael Faraday in 1857 when he prepared gold nanoparticles and observed that nanostructured gold produced red color. This distinct feature of nanoparticles could be due to very small size. NPs are very small compared to the wavelengths of light, hence absorb light in the blue-green portion of the spectrum (~450 nm) and reflect the red light (~700 nm) thus yield a rich red color. NPs also possess very high surface to mass ratio that could be utilized in several application areas wherein a very high surface area is required. Nanoparticles witnessed tremendous growth in research and application areas especially in medicine in twentieth century after discovery of carbon nanotubes in 1991. Nanoparticles have been explored in medicine as targeted delivery carriers to deliver macromolecules such as proteins, enzymes, to the target organ up to cellular levels. Of late, these carriers have been employed to treat several tumors owing to its capacity to deliver chemotherapeutic agents to the tumor cells only thus improving efficacy and minimizing side effects of anticancer agents.

Evaluation of Cardioprotective activity of Asparagus racemosus against Doxorubicin induced cardiotoxicity in albino rats: an experimental study

Background: Cardiotoxicity is one of the most feared side effects of anticancer agents like Doxorubicin. Asparagus racemosus is a widely used medicinal plant in Indian system of medicine known for its antioxidant activity. In certain studies ethanol extract of Asparagus racemosus has shown to possess cardioprotective activity in experimental animals while in some other studies cardioprotective potential of Asparagus racemosus has not been demonstrated. Therefore, due to the controversial action, the present study was designed to explore the cardioprotective effect of aqueous effect of Asparagus racemosus against doxorubicin induced cardiotoxity.Methods: Following approval from Institutional Animal Ethics Committee of L.L.R.M Medical College registered under CPCSEA, India, this study was conducted in which 30 rats were randomized into five groups of six rats each. Group I received 2 ml/kg b.w. normal saline p.o for 21 days, group II apart from receiving pellet diet and normal saline for 21 days were treated with Doxorubicin in a single dose of 20 mg/kg intraperitoneally on the 21st day, group III and group IV received aqueous extract of Asparagus racemosus in doses of 250 mg/kg/day and 500 mg/kg/day respectively p.o. for 21 days followed by administration of Doxorubicin (20 mg/kg i.p.) on the 21st day, Group V received Carvedilol in doses of 30 mg/kg/day p.o. for 21 days followed by administration of Doxorubicin (20mg/kg i.p) on the 21st day. Then they were anaesthetized and blood sample was collected from abdominal aorta for performing blood test i.e. Creatinine kinase MB fraction (CK-MB), Lactate dehydrogenase (LDH), Serum glutamate oxaloacetate transaminase (SGOT), Serum glutamate pyruvate transaminase (SGPT). After blood collection the animals were sacrificed and heart was dissected out for histopathological study. The data obtained was organized and analysed by suitable statistical methods i.e. ANOVA followed by Post Hoc test.Results: CK-MB, LDH, SGOT and SGPT levels were found to be significantly raised (p<0.001) in Doxorubicin treated group. Asparagus racemosus pretreated groups exhibited significant limitation (p<0.001) in rise in levels of CK-MB,LDH,SGOT and SGPT levels in a dose dependent manner following Doxorubicin administration which were comparable to the group treated with the standard cardioprotective drug Carvedilol. Histopathological changes further corroborated cardioprotective potential of Asparagus racemosus.Conclusions: The present study concluded that aqueous extract of Asparagus racemosus possess cardioprotective potential against Doxorubicin induced cardiotoxicity.

Nail changes due to chemotherapy: a prospective observational study of 129 patients.

Nail changes due to systemic drugs are common, especially with anticancer treatments due to involvement of nail plate, nail bed and periungual area. To study the pattern of nail changes occurring due to chemotherapy in patients suffering from various malignancies. A prospective, observational study was conducted at various health care centres, Nashik, India, for 15months. The timing of administration of chemotherapy and onset of nail changes were recorded and evaluated by a dermatologist at regular interval. A total of 129 diagnosed cases of various malignancies who received chemotherapy were included. The most common malignancy noted was breast cancer, that is n=42 (32.5%) followed by oral cancer, that is n=24 (18.6%). Chemotherapy agents included taxanes (n=54), cyclophosphamide (n=42) and prednisolone (n=28). Nail changes were noted in 92 patients (71.3%). The most common nail changes observed were chromonychia (n=70, 54.26%), followed by nail dystrophy (n=38, 29.45%). Nail toxicity is quite common side effect of anticancer agents. Nail changes due to chemotherapy depend on the nail structure involved and the severity of insult. Awareness among dermatologists and oncologists of these nail changes and their culprit agent can promote early diagnosis and may avoid inadvertent measures.

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop

The US Food and Drug Administration and the Critical Path Institute’s Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug’s overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.

Vitamin D-Loaded Nanostructured Lipid Carrier (NLC): A New Strategy for Enhancing Efficacy of Doxorubicin in Breast Cancer Treatment

ABSTRACTThe dangerous dose-dependent side effects of anticancer agents triggered the finding of new approaches for elevated chemotherapy efficacy. This study investigated the potential application of nanostructured lipid careers (NLCs) in increasing vitamin D3 (VitD) effectiveness in breast cancer cell (MCF-7) in concurrent administration with doxorubicin (Dox). VitD-loaded NLCs were characterized by particle size, zeta potential, Fourier transform infrared spectroscopy, and scanning electron microscope. Cytotoxicity and molecular effects of formulation were evaluated by MTT, DAPI staining, flow cytometry, and real-time quantitative PCR assays. The formulation revealed mean particle size of 87±5 nm with a polydispersity index of 0.24 confirmed by SEM images. The IC50 values for VitD and Dox were 1.3 ± 0.04 and 0.65 ± 0.05 µM, respectively. VitD-loaded NLCs decreased the percentage of cell proliferation from 49 ± 7.2% to 37 ± 5.1% (P < 0.05). Cotreatment of the cells with VitD-loaded NLCs and Dox caused over a twofold increase in the percentage of apoptosis (P < 0.05). Gene expression profile demonstrated a significant decrease in antiapoptotic factor survivin along with increase in proapoptotic factor Bax mRNA levels. Overall, our results introduced the NLC technology as a novel strategy to elevate the efficacy of chemotherapeutics in breast cancer.

Extraction and encapsulation of prodigiosin in chitosan microspheres for targeted drug delivery

The encapsulation of drugs in polymeric materials has brought opportunities to the targeted delivery of chemotherapeutic agents. These polymeric delivery systems are capable of maximizing the therapeutic activity, as well as reducing the side effects of anti-cancer agents. Prodigiosin, a secondary metabolite extracted from the bacteria, Serratia marcescens, exhibits anti-cancer properties. Prodigiosin-loaded chitosan microspheres were prepared via water-in-oil (w/o) emulsion technique, using glutaraldehyde as a cross-linker. The morphologies of the microspheres were studied using scanning electron microscopy. The average sizes of the microspheres were between 40μm and 60μm, while the percentage yields ranged from 42±2% to 55.5±3%. The resulting encapsulation efficiencies were between 66.7±3% and 90±4%. The in-vitro drug release from the microspheres was characterized by zeroth order, first order and Higuchi and Korsmeyer-Peppas models.

A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice.

Intestinal mucositis (IM) is a common side effect of anticancer agents. Despite polychemotherapy use in clinical practice, the pathogenesis of IM has been investigated in single drug injection animal models. However, the progression of IM could vary according to drug regimens. Thus, we aimed to develop a new experimental mucositis model induced by combining irinotecan and 5-fluorouracil (5-FU) treatments. IM was induced in male C57BL/6 mice by the intraperitoneal administration of either 0.9% saline (5mL/kg), irinotecan (IRI, 30 or 45mg/kg), 5-FU (25, 37.5, or 50mg/kg), or the combination of these doses (IRI+5-FU) for 4days. Animal survival, body mass variation, and diarrhea scores were evaluated daily. On the 7th day, the mice were euthanized, and intestinal samples were collected for histopathology and morphometric analysis, as well as for the determination of myeloperoxidase activity and cytokine dosage (TNF-α and IL-6). The optimal dose combination that induced IM and presented no substantial mortality on the 7th day was IRI (45mg/kg)+5-FU (37.5mg/kg), which was used for subsequent studies. IRI and 5-FU in combination induced significant diarrhea, body weight loss, intestinal damage, inflammatory cell infiltration, and increased levels of cytokines when compared with other groups (P<0.05). Neither IRI nor 5-FU alone induced IM. We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.

Functional liposomes in the cancer-targeted drug delivery.

Cancer is considered as one of the most severe health problems and is currently the third most common cause of death in the world after heart and infectious diseases. Novel therapies are constantly being discovered, developed and trialed. Many of the current anticancer agents exhibit non-ideal pharmaceutical and pharmacological properties and are distributed non-specifically throughout the body. This results in death of the both normal healthy and malignant cells and substantially leads to accruing a variety of serious toxic side effects. Therefore, the efficient systemic therapy of cancer is almost impossible due to harmful side effects of anticancer agents to the healthy organs and tissues. Furthermore, several problems such as low bioavailability of the drugs, low drug concentrations at the site of action, lack of drug specificity and drug-resistance also cause many restrictions on clinical applications of these drugs in the tumor therapy. Different types of the liposomal formulations have been used in medicine due to their distinctive advantages associated with their structural flexibility in the encapsulation of various agents with different physicochemical properties. They can also mediate delivery of the cargo to the appropriate cell type and subcellular compartment, reducing the effective dosage and possible side effects which are related to high systemic concentrations. Therefore, these novel systems were found very promising and encouraging dosage forms for the treatment of different types of cancer by increasing efficiency and reducing the systemic toxicity due to the specific drug delivery and targeting.

Oxaliplatin neurotoxicity involves peroxisome alterations. PPARγ agonism as preventive pharmacological approach.

The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) antagonist G3335 (30 µM) induced a similar peroxisomal impairment suggesting a relationship between PPARγ signaling and oxaliplatin neurotoxicity. The PPARγ agonist rosiglitazone (10 µM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg−1 per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of peroxisomes in oxaliplatin-dependent nervous damage and suggest PPARγ stimulation as a candidate to counteract oxaliplatin neurotoxicity.

Plasma stable, pH-sensitive fusogenic polymer-modified liposomes: A promising carrier for mitoxantrone

pH-sensitive liposomes are designed to undergo acid-triggered destabilization. In the present study, we prepared polymer-modified, plasma stable, pH-sensitive fusogenic mitoxantrone liposomes to increase efficacy and selectivity on cancer cell lines. Conventional liposomes were prepared using cholesterol and dipalmitoyl-sn-glycero-3-phosphatidylethanolamine. Dioleoylphosphatidylethanolamine and a cholesteryl derivative, poly(monomethylitaconate)-co-poly(N,N-dimethylaminoethyl methacrylate) (PMMI-co-PDMAEMA), were used for the preparation of pH-sensitive fusogenic liposomes. Using polyethylene glycol (PEG)-poly(monomethylitaconate)-CholC6 (PEG-PMMI-CholC6) copolymers instead of cholesterol introduced pH-sensitive and plasma stability properties simultaneously in prepared liposomes. All formulations were prepared by thin film hydration method and subsequently, pH-sensitivity and stability in human serum were evaluated. The ability of pH-sensitive fusogenic liposomes to enhance the mitoxantrone cytotoxicity and selectivity in cancerous cell lines was assessed invitro compared to normal cell line using human breast cancer cell line (MCF-7), human prostate cancer cell line (PC-3), and human umbilical vein endothelial cells line. Results revealed that both PMMI-co-PDMAEMA and PEG-PMMI-CholC6-based formulations showed pH-sensitive property and were found to rapidly release mitoxantrone under mildly acidic conditions. Nevertheless, only the PEG-PMMI-CholC6-based liposomes preserved pH-sensitivity after incubation in plasma. Mitoxantrone loaded-pH-sensitive fusogenic liposomes exhibited a higher cytotoxicity than the control conventional liposomes on MCF-7 and PC-3 cell lines. On the contrary, both pH-sensitive fusogenic liposomes showed lower cytotoxic effect on human umbilical vein endothelial cell line. Plasma stable, pH-sensitive fusogenic liposomes are promising carriers for enhancing the efficiency and selectivity, besides reduction of the side effects of anticancer agents.

In vitro and in vivo properties of usnic acid encapsulated into PLGA-microspheres

Microparticles will probably play a promising role in the future of chemotherapy. These polymeric delivery systems are capable of maximizing the therapeutic activity while reducing side effects of anti-cancer agents. Usnic acid (UA) is a secondary metabolite produced by lichens, which exhibits an anti-tumour activity. In this study, PLGA-microspheres containing usnic acid from Cladonia substellata were prepared by the double emulsion method, with or without PEG as stabilizer. The morphology of the microspheres was examined by optical and scanning electron microscopy. The in vitro kinetic profile of usnic acid loaded-microspheres was carried out by dissolution testing. The usnic acid content was analysed by HPLC. The cytotoxicity of free and encapsulated usnic acid was evaluated against HEp-2 cells using the MTT method. The anti-tumour assay was performed in mice against Sarcoma-180 tumour (UA 15 mg kg−1 weight body/day) during 7 days. Animals were then sacrificed and tumour and organs were excised for histopathological analysis. Microspheres presented a smooth spherical surface with a mean diameter of 7.02 ± 2.72 µm. The usnic acid encapsulation efficiency was ∼100% (UA 10 mg 460 mg−1 microspheres). A maximum release of 92% was achieved at the fifth day. The IC50 values for free and encapsulated usnic acid were 12 and 14 µg ml−1, respectively. The encapsulation of usnic acid into microspheres promoted an increase of 21% in the tumour inhibition as compared with the free usnic acid treatment. In summary, usnic acid was efficiently encapsulated into PLGA-microspheres and the microencapsulation improved its anti-tumour activity.

An experimental study on the pharmacokinetics of 5-fluorouracil regional chemotherapy for pancreatic cancer.

Recently a few centers reported promising results of regional intra-arterial chemotherapy for pancreatic cancer. However, the detailed pharmacokinetics and the side effects of anticancer agents remain unclear. Catheters were introduced into the gastroduodenal artery and the splenic artery of dogs. In group I, arterial infusion of 5-fluorouracil (5-FU) was performed over 10 minutes. In group II, 5-FU was infused systemically. In group III, an intra-arterial infusion was repeated weekly three times. Blood samples and liver and pancreas tissue samples were obtained to determine 5-FU levels. In a subset of each group, the pancreas, duodenum, and liver were excised for histological analyses. Immediately after the infusion of 5-FU, the portal level in group I was higher than that in group II. However, the mean systemic level in group I was lower than in group II. The mean tissue concentration in the pancreas in group I was significantly higher than that of group II. Histological examination revealed no microscopic alterations after treatment in all groups, including group III. This fundamental study suggested that intra-arterial chemotherapy of 5-FU for pancreatic cancer allows higher regional drug delivery without adverse effects on normal regions of the pancreas, the duodenum, and the liver.

Apoptosis of bladder cancer cells induced by short-term and low-dose Mitomycin-C: Potential molecular mechanism and clinical implication

Adjuvant chemotherapies have been used to prevent recurrence of bladder transitional cell carcinoma (TCC), but their efficacies are variable due to the side effects of anti-cancer agents and the drug resistant property of the target cells. To provide experimental evidence for improving clinical management of TCCs, two human TCC cell lines, EJ and BIU, were treated for 1 or 2 h by 50, 100, 150 and 200 micro g/ml, respectively and their growth and death patterns were elucidated in 12-h intervals. The status of Fas, FasL and caspase-3 in the two cell lines were analyzed with immunocytochemical staining and Western blot hybridization, and their potential link to MMC-induced cell death was investigated by treating the cells with anti-Fas antibody (150 ng/ml) and by incubating the cells with an inhibitor of caspase-3 related proteases Ac-DEVO-CHO (250 micro M) 1 h before 100 micro g/ml MMC treatment. The results demonstrated that the lower dose (100 micro g/ml) and short-term (1 h) MMC treatment could induce sufficient apoptosis in EJ and BIU populations within 48 or 60 h. Constitutive soluble and membrane Fas and FasL were found in both cell lines, and caspase-3 could be upregulated after MMC treatment. Anti-Fas antibody could commit the target cells to die of apoptosis, while Ac-DEVD-CHO inhibited MMC-induced apoptosis. Our data thus suggest that MMC-induced apoptosis in EJ and BIU cells is mediated by Fas and upregulation and activation of caspase-3 is an essential element for the apoptotic process. Reduced dose and short-term MMC strategy would be of practical value either in determining the apoptotic susceptibility of individual TCC cases or in the clinical instillation of urothelial cancers.

Pharmacological separation of the expression of tissue transglutaminase and apoptosis after chemotherapeutic treatment of HepG2 cells.

Chemotherapeutic drugs are known to eliminate cancer cells by inducing apoptosis. Tissue transglutaminase (tTG), a frequent player in apoptotic processes, is markedly induced in drug-resistant cancer cells. To better understand the action of apoptosis-inducing drugs, our study elucidates changes in the expression of tTG in the early phase of cell death, before the downstream events of apoptosis. We demonstrate that HepG2 cells uniformly induce both tTG mRNA and enzyme activity upon treatment with cisplatin, doxorubicin, and bleomycin, chemotherapeutic agents with different modes of action. The expression of fas ligand, caspase3 and baxalpha changes differentially or remain unaffected. tTG expression did not change significantly after administration of either the peroxisome proliferator activated receptor-alpha agonist WY14643 or the retinoid X receptor-specific analog LG 100268. However, both compounds blocked drug-induced tTG induction without affecting the extent of cell death. The pleiotropic cytokine interleukin-6 effectively rescued hepatoma cells from apoptosis while tTG induction still took place, along with the induction of antiapoptotic transcripts bcl-x(L), gp130, and her2/neu. These results suggest that the induction of tTG, although present in drug-induced apoptosis, is pharmacologically dissociable from the early, initiating events of apoptosis. Blocking the induction of tTG during drug-induced cell death may alleviate limiting side effects of anticancer agents, including fibrosis and neuropathies.