Active Cytotoxic Agents Research Articles

Taxane chemotherapy treatment for metastatic breast cancer

SUMMARY The taxanes, paclitaxel, docetaxel and nab-paclitaxel, are among the most active cytotoxic agents for treatment of breast cancer. Significant progress has been made in addressing taxane dose and schedule in both early-stage and metastatic disease. Several studies have clarified the role of retreatment with taxanes in recurrent breast cancer patients previously treated with taxane-containing regimens. In addition, the advent of nab-paclitaxel, designed to reduce allergic reactions and enhance drug delivery to tumor cells, has provided additional therapeutic options. This article summarizes the uses of taxanes in the treatment of metastatic breast cancer.

The composition and end-group functionality of sterically stabilized nanoparticles enhances the effectiveness of co-administered cytotoxins.

Diffusion of active cytotoxic agents throughout an entire solid tumour is a particular challenge to successful drug delivery. Here we show the simple and robust generation of non-toxic, 10-15 nm superparamagnetic iron oxide nanoparticles (SPIONs) that have been sterically stabilized by either 100% anionic or 100% cationic or 100% neutral end-functionalized steric stabilizers or by novel combinations of cationic and neutral end-functionalized polymer. When these nanoparticles were co-administered with various anti-cancer drugs, a significant increase in the diffusion and effectiveness of the cytotoxin in a 3-dimensional model of a solid tumour was shown for specific combinations of surface functionality and cytotoxin. The critical determinant of enhanced cytotoxin diffusion and effectiveness was the end functionality of the steric stabilizers and not the core composition (either iron oxide, silica or gold). We provide evidence that SPIONs stabilized with heterogeneous steric stabilizers enhance nuclear uptake of doxorubicin across multiple cell layers.

Effects of organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione on cisplatin induced nephrotoxicity and genotoxicity: an investigation of the influence of the compound on oxidative stress and antioxidant enzyme system

Cisplatin is one of the most active cytotoxic agents used in the treatment of cancer. However, cisplatin therapy is also associated with severe side effects like nephrotoxicity and genotoxicity. Free oxygen radicals are known to play a major role in cisplatin induced toxicities. Selenium is believed to be an important trace element and dietary antioxidant because of its ability to scavenge free oxygen radicals, thereby preventing cells from oxidative stress. The purpose of this study is to evaluate the protective role of a novel naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione against cisplatin induced toxicities in Swiss albino mice. Cisplatin was administered intraperitoneally (5mg/kg b.w.) and the organoselenium compound was given by oral gavages (3mg/kg b.w.) in concomitant and pretreatment schedule. The results showed that the test compound substantially reduced cisplatin induced reactive oxygen species generation and lipid peroxidation in kidney as well as blood urea nitrogen and creatinine levels in serum. Treatment with organoselenium compound was also able to restore the renal antioxidant system by modulating the cisplatin induced depleted activities of glutathione S-transferase, thioredoxin reductase, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione level. In addition, the organoselenium compound could efficiently minimize cisplatin induced chromosomal aberrations in bone marrow cells and extent of DNA damage in lymphocytes. Furthermore, the chemoprotective efficacy of the compound against cisplatin induced toxicity was confirmed by histopathological evaluation. The results suggest that the organoselenium compound has the potential to protect against cisplatin induced nephrotoxicity and genotoxicity in part by scavenging reactive oxygen species and by up regulating the antioxidant enzyme system.

Synthesis, cytotoxic evaluation, docking and in silico pharmacokinetic prediction of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone thiosemicarbazones

In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1, 2-naphthoquinone thiosemicarbazones were synthesized and characterized using FT-IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell lines (Hep-G2, MG-63 and MCF-7) using the MTT assay. Significant anticancer activity was observed for several members of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS13) were active cytotoxic agents in all three cancer cell lines, with IC50 values in the range of 3.5–6.4 µM. Further evaluation of some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A). Docking experiments showed a good correlation between the predicted glide scores and the IC50 values of these compounds. In silico ADME studies revealed that these compounds can be used for second generation development.

Antitumor effectiveness and toxicity of cisplatin-loaded long-circulating and pH-sensitive liposomes against Ehrlich ascitic tumor

Cisplatin (CDDP) is one of the most active cytotoxic agents commonly used in the treatment of peritoneal carcinomatosis. The disadvantages of its clinical use are systemic side-effects, such as nephrotoxicity and myelotoxicity. Long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP) were developed by our research group aiming to promote the release of CDDP near the tumor as well as decreasing toxicity. The aim of this study was to evaluate the antitumor efficacy and toxicity of SpHL-CDDP after intraperitoneal administration in initial or disseminated tumor-bearing mice, at a dose of 12 mg/kg. The survival was monitored and blood samples were collected for biochemical and hematological analysis. Kidneys, liver and spleen were removed for histopathological examination. Tumor cells were evaluated for cellular viability and cell cycle. The survival of animals treated with SpHL-CDDP was higher than those treated with free CDDP. The cell death caused by treatment with SpHL-CDDP occurred through induction of apoptosis, with a cell cycle arrest at the G0/G1 phase. The treatment of mice presenting initial cancer with both formulations provoked a suppression of granulocytes. Mice treated with free CDDP also showed a decrease in platelet count, which suggests a high myelotoxicity. In an advanced cancer model, SpHL-CDDP treatment allowed an improvement of the immune response. Mice affected by cancer at an early stage and treated with free CDDP or SpHL-CDDP showed a lower urea/creatinine index compared with the saline control group. These findings indicate that both treatments were able to reduce the renal damage caused by peritoneal carcinomatosis. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed a discrete morphological alteration, while tubular necrosis was observed for free CDDP-treated mice. Concerning hepatotoxicity, no alteration in clinical chemistry parameters was observed. These findings reveal that SpHL-CDDP can improve the antitumor efficacy and decrease renal and bone marrow toxicity.

Synthesis, characterization, in vitro anticancer activity, and docking of Schiff bases of 4-amino-1,2-naphthoquinone

A series of Schiff bases of 4-amino-1,2-naphthoquinone were synthesized, purified, characterized, and evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G2, MG-63, and MCF-7). The cells were dosed with these Schiff bases at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Significant anticancer activities were observed in vitro for some members of the series and compounds 4-(3,4,5-trimethoxybenzylideneamino)naphthalene-1,2-dione (S10) as well as 4-(4-hydroxy-3-methoxybenzylideneamino)naphthalene-1,2-dione (S13) are active cytotoxic agents against different cancer cell lines with IC50 values in the range of 5.91–9.98 μM. The structures of synthesized compounds were established by spectroscopic (FT-IR, 1H NMR, 13C NMR) and elemental analysis. To study the molecular basis of interaction and affinity of binding of the target molecules, all the compounds were docked into the ATPase domain of Topoisomerase-II (TP-II) by using Schrodinger molecular modeling software package. Docking experiments showed a good correlation between their predicted glide scores and the observed IC50 values of synthesized compounds. Structure–activity relationships indicated that presence of electron donating groups on phenyl ring of Schiff bases enhances the activity but Schiff base with electron withdrawing substituents on phenyl ring shows diminished activity.

Peripheral T cell lymphoma: clinical utility of romidepsin

Correspondence: Jasmine Zain NYU Langone Medical Center, 160 East 34th Street, 11th Floor, New York, NY 10016, USA Tel +1 212 731 6544 Fax +1 212 731 5540 Email jasmine.zain@nyumc.org Introduction: Direct therapeutic targets, such as aberrant tumor cell genes and tumor cell markers, have been the focus of cancer treatment for more than 50 years. The resulting damage to normal cells and emergence of drug-resistant tumor cells after exposure to conventional chemotherapy have led researchers to study indirect targets, like the tumor vasculature. A more recent indirect approach involves targeting the epigenetic modifiers, DNA methyltransferase and histone deacetylase. Histone deacetylase inhibitors have been shown to be active cytotoxic agents in T cell lymphoma. The current treatments approved by the US Food and Drug Administration for relapsed cutaneous T cell lymphoma are vorinostat and romidepsin. The diversity and rarity of peripheral T cell lymphomas present a challenge for effective treatment. With their poor overall survival rate, new targeted therapies need to be developed.

P-0247 Cost-Effectiveness of Bevacizumab Versus Cetuximab Versus Panitumumab Combined with First-Line Folfox for Metastatic Colorectal Cancer in Brazil

ABSTRACT Introduction Treatment of metastatic colorectal cancer (mCRC) involves the use of active cytotoxic drugs and biological agents. The ideal combination in first-line therapy should be defined considering the costs, efficacy and tolerability of each regimen. The objective of this analysis, from the Brazilian public health system perspective, was to evaluate the cost-effectiveness of adding biological agents to the FOLFOX regimen in first-line treatment of mCRC. Methods A Markov model was developed to simulate mCRC patient outcomes and costs throughout first- and subsequent lines of treatment, comparing bevacizumab vs cetuximab vs panitumumab combined with the FOLFOX regimen in first-line treatment. All patients were supposed to have KRAS wild-type tumors, and be treated with the FOLFIRI regimen in second-line treatment. Data for model parameters were derived from MRC-COIN, OPUS, NO16966, and PRIME randomized studies projecting outcomes for a lifetime period. Resource use included drugs, physician visits, scans, laboratory exams, hospitalizations, and treatment of adverse events. The associated costs were obtained from price tables regulated by Brazilian Ministry of Health and are expressed in US dollars. The incremental cost per life-year gained was calculated comparing all strategies to FOLFOX alone. Results The addition of bevacizumab, cetuximab and panitumumab to first-line FOLFOX resulted in 0.08, 0.20 and 0.16 additional life-years, respectively, and incremental cost effectiveness ratios (ICERs) of $492,000, $300,000 and $317,000 per LY, respectively. The use of cetuximab was dominant over bevacizumab and panitumumab. The ICERs are mainly driven by the risk of death or progression during first-line treatment and the acquisition cost of biological agents. Conclusion The economic evaluation demonstrates that all available biologic agents are not cost-effective in combination to first-line FOLFOX regimen for wtKRAS mCRC patients. From a global perspective, the use of cetuximab was dominant over bevacizumab and panitumumab, showing that FOLFOX plus cetuximab could be the preferred combination in this population.

Synthesis of Chalcones with Anticancer Activities

Several chalcones were synthesized and their in vitro cytotoxicity against various human cell lines, including human breast adenocarcinoma cell line MCF-7, human lung adenocarcinoma cell line A549, human prostate cancer cell line PC3, human adenocarcinoma cell line HT-29 (colorectal cancer) and human normal liver cell line WRL-68 was evaluated. Most of the compounds being active cytotoxic agents, four of them with minimal IC50 values were chosen and studied in detail with MCF-7 cells. The compounds 1, 5, 23, and 25 were capable in eliciting apoptosis in MCF-7 cells as shown by multiparameter cytotoxicity assay and caspase-3/7, -8, and -9 activities (p < 0.05). The ROS level showed 1.3-fold increase (p < 0.05) at the low concentrations used and thus it was concluded that the compounds increased the ROS level eventually leading to apoptosis in MCF-7 cells through intrinsic as well as extrinsic pathways.

Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells.

Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS-resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5-trihydroxy-trans-stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti-inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS-resistant HCT-116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 µg/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 µg/ml). RSVL treatment showed anti-proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS-resistant HCT-116 CRC cells, with a half maximal inhibitory concentration of 4.20 µg/ml and 4.72 µg/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS-resistant HCT-116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS-resistant HCT-116 CRC cells.

Synthesis, characterization and cytotoxic activity of new salicylaldehyde benzoylhydrazone derivatives as potential anti-proliferative agents

Three new hydrazones, derivatives of salicylaldehyde benzoylhydrazone, were synthesized as potential anti-proliferative compounds. The structure of the new compounds was characterized by elemental and thermo-gravimetric analyses, IR, 1H and 13C-NMR spectroscopy and quantum chemical calculations. The cytotoxic effects of new hydrazones were examined on a wide spectrum of human tumor cell lines. The obtained results revealed that all compounds proved to be equipotent or moreactive than cisplatin, and far more activethan another utilized anticancer drug, melphalan. On the basis of IC50 values the compound 3-methoxy-salicylaldehyde isonicotinoylhydrazone (mSIH) was found to be the most active cytotoxic agent at all cell lines.

Synthesis, Molecular docking and Biological evaluation of 4-Cycloalkylidineamino 1, 2-Naphthoquinone Semicarbazones as Anticancer agents

ObjectiveIn an effort to etablish new candidates with improved antineoplastic activity, 4-cycloalkylidineamino 1,2-naphthoquinone semicarbazones were synthesized, characterized and evaluated for anticancer activity. MethodThe desired compounds were synthesized by condensation of 4- amino1, 2-naphthoquinone with cyclic ketones and further subsequent reaction of this product with semicarbazide hydrochloride. Compounds were characterized by FT-IR, 1H NMR, 13C NMR, elemental analysis and screened for antiproliferative activity against three human cancer cell lines (HepG2, MG-63 and MCF-7) by MTT assay using doxorubicin as standard. Docking was performed by using the Glide 5.7 integrated with Maestro 9.2 (Schrödinger, LLC, 2011) to understand the binding preference of synthesized compounds with target enzyme topoisomerase-II. Results4-(cyclohexylideneamino) [1, 2] naphthoquinone 2-semicarbazone was found to be most active cytotoxic agent against all cancer cell lines with IC50 values in the range of 5.58–6.31 µM. Results of molecular docking were also well correlated in vitro cytotoxicity assay. Insilico ADME studies revealed the drug likeliness of compounds. ConclusionsThe synthesized compounds were found to have significant anticancer activity and able to enter in higher phases of the drug development process due to favorable pharmacokinetic properties.

Do we need biomarkers to predict the benefit of adding adjuvant taxanes for treatment of breast cancer?

The current understanding of the molecular biology of breast cancer presents an extremely complex portrait of the disease. Based on this knowledge, considerable efforts are being made to identify biomarkers that will predict the response to a specific treatment while minimizing the risk of unnecessary side effects. In breast cancer, the Ki67 index has been associated with poor prognosis and might play a relevant role in predicting benefit from adjuvant docetaxel, as observed in the article accompanying this editorial. Taxanes are one of the most active cytotoxic agents for breast cancer. However, the role of taxane-based chemotherapy as adjuvant treatment of early breast cancer remains controversial in some subsets of patients. For this reason, the Ki67 index might help to better define the group of patients who could have the optimal benefit.

Synthesis, Characterization and Antiproliferative Activity of 1,2-Naphthoquinone and Its Derivatives

In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, ¹H NMR, ¹³ C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G₂ for liver sarcoma, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone, 1,2-naphthoquinone-2-semicarbazone, 4-amino-1,2-naphthoquinone 2-thiosemicarbazone and 4-amino-1,2-naphthoquinone-2-semicarbazone are active cytotoxic agents against different cancer cell lines with IC₅₀ values in the range of 5.73-17.67 μM. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2-naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC₅₀ values of all these compounds.

Targeted Taxane Delivery Systems: Recent Advances

Taxanes (paclitaxel and docetaxel) are among the most active cytotoxic agents in use in oncology, being widely used in adjuvant and advanced treatment settings in multiple tumor types. Due to the impressive benefits offered by the taxanes, different strategies are in development, aimed at reducing their systemic toxicity and the need for premedication, while improving anti-tumor spectra and treatment efficacy. Although a remarkable amount of effort has been aimed at overcoming delivery difficulties, very few compounds have reached clinical trials, and some of those few have failed advanced trials. This mini-review reports the most recent developments in advanced taxane delivery approaches, with particular focus on receptor-targeted delivery systems. Keywords: Taxanes, conjugates, micelles, nanoparticles, chemotherapy, cancer, drug delivery, cancer cells, EGFR, POLYMERIC MICELLES

Gemcitabine Is An Active Agent In Acquired Human Immunodeficency HIV Related Lymphomas

Abstract 4951Gemcitabine is a cell cycle phase specific cytotoxic agent. It’s phosphorylated products inhibit ribonucleotide reductase an enzyme responsible for DNA synthesis. It also competes with the incorporation of deoxycytosine triphospate (dCTP) into the DNA strands. After Gemcitabine is incorporated into the DNA the growing DNA strands will stop. Gemcitabine has proven to be an active cytotoxic agent in the treatment of lymphomas, either as a single agent or in combination with platinum and dexamethsone. Gemcitabine efficacy has not been investigated in the treatment of HIV patients with Lymphomas. The purpose of this abstract is to show our experience with this agent in HIV related lymphomas. This summarize the experience with three patients. First patient is 42 years old white male with diffuse large B cell type Non-Hodgkin’s Lymphoma involving the right psoas muscle and invading the pelvic nerve roarts causing intractable pain that has not been resonsive to CHOP (four cycles), the third patient is a 55 years old hispanic female with stage IV Hodgkin’s Lymphoma (mixed cellularity) that has failed ABVD × 6 cycles and progressed in less than two months from completion of treatment. This patient presented with B symptoms and cachexia at relapse. The third patient is 50 years old black male with stage III Immunoblastic B Cell Lymphoma who failed EPOCH. All patients were on HAART medication and viral load were undetectable in two of these patient (2,3). The first patient received Gemcitabine alone. With two weekly doses of 1000mg/M2 the pain resolved and he stopped narcotics and was refered to other institution for autologus bone marrow transplant. The second patient received two cycles of Gemcitabine, Cisplatin and Decadron within one dose the B symptoms and the sever bony pain have disappeared completely. The third patient completed six cycles of treatment; each cycle is of twenty eight days duration; Gemcitabine 1000mg/M2 given IV on week one and two(day1) and Cisplatinum 80/M2 mg given IV on day one with decadron 40 mg po with each chemotherapy treatment. This patient has been in complete remisson and is alive after three years. In conlusion: Gemcitabine is an active agent that can be used safely in HIV/AIDS patients with lymphomas with good results. Disclosures:No relevant conflicts of interest to declare.

Protective effect of erythropoietin against cisplatin-induced nephrotoxicity in rats: antigenotoxic and antiapoptotic effect

Cisplatin (Cisp) is an active cytotoxic agent that was found efficient in the treatment of various types of solid tumors. Its nephrotoxic effect has been very well documented in clinical oncology. Erythropoietin (EPO), a renal cytokine-regulating hematopoiesis, has recently been shown to exert important cytoprotective effects in many experimental injuries. The aim of this study was to explore whether EPO would protect against Cisp-induced apoptosis in rat kidney. Adult Wistar rats were treated with saline solution as the control group, Cisp alone, EPO alone, or EPO with Cisp in different treatments: 1) EPO and Cisp simultaneously administrated to animals as a cotreatment; 2) EPO administered 24 hours before Cisp as a pretreatment; and 3) EPO administered 5 days after Cisp injection as a post-treatment. Our results have shown that Cisp induced renal failure, characterized with a significant increase in serum creatinine and blood urea nitrogen (BUN) concentrations. Cisp promoted kidney DNA fragmentation and apoptotic cell death. Apoptosis was revealed by an enhancement of proapoptotic protein (e.g., p53 and Bax) levels, decrease in antiapoptotic proteins (e.g., Bcl2 and Hsp27), and increase in caspase-3 activity. Treatments with EPO restored creatinine and BUN levels and inhibited Cisp-induced DNA damage in the kidney. Apoptosis was also reduced by the upregulation of antiapoptotic protein expressions, downregulation of proapoptotic protein levels, and reduction of caspase-3 activity.

Synthesis and Anticancer Activity of Some New S-Glycosyl and S-Alkyl 1,2,4-Triazinone Derivatives

A series of S-glycosyl and S-alkyl derivatives of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (1)were synthesized using different halo compounds such as preacetylated sugar bromide, 4-bromobutylacetate, 2-acetoxyethoxy-methyl bromide, 3-chloropropanol, 1,3-dichloro-2-propanol, epichlorohydrin, allyl bromide, propargyl bromide, phthalic and succinic acids in POCl3. The structures of the synthesized compounds have been deduced from their elemental analysis and spectral (IR, 1H-NMR, and 13C-NMR) data. Some of the synthesized compounds were screened as anticancer agents. Significant anticancer activities were observed in vitro for some members of the series, and compounds 4-Amino-3-(3-hydroxypropylthio)-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (12) and 3-(4-Oxo-3-(2-(2-thienyl)vinyl)-4H-[1,3,4]thiadiazolo-[2,3-c][1,2,4]tr-iazin-7-yl)propanoic acid (18) are active cytotoxic agents against different cancer cell lines.

The role of sensitivity of ALA (PpIX)-based PDT on Human embryonic kidney cell line (HEK293T)

Present study evaluates the effects of photodynamic therapy (PDT) with aminolevulinic acid (5-ALA) as photo sensitizer using Human embryonic kidney (HEK293T) cell line as an experimental model. Porphyrins derivatives are used as active cytotoxic antitumor agents in PDT. Above mentioned cell line were irradiated with red light (a diode laser, λ = 635 nm) at different doses (0–160 J/cm2) of light. The influence/effectiveness of incubation time, various concentrations of aminolevulinic acid (5-ALA) and light doses on the cellular viability was studied. HEK293T cells were deliberated by exposing the ALA-PpIX (0–1000 μg/ml) of concentrations. The optimal uptakes of photosensitizer (PS) in cell lines were investigated by means of spectro photo metric measurements. Cells viability was determined by means of neutral red assay (NRA). It was observed that alone, neither photosensitizer nor light dose have significant effect on cells viability, but optimal concentration of PS along with suitable dose of light exhibit effective impact on the viability of cell. Our results showed that light doses of 40 J/cm2 demonstrates effective PDT outcome for HEK293T cell line when incubated with 400 μg/ml, with wrapping up view that HEK293T cell line is very sensitive to ALA-mediated PDT as compared to cell line published in our data. At the end results has been verified by using reactive oxygen species (ROS) measure test.

Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice

Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity.