Active Antitumor Agent Research Articles

Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII

A series of novel N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9–41 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed KI in the range of 87–6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7–416 nM and against hCA XII at range of 0.96–540 nM. Compounds 10, 12–14, 16, 18–20, 24–26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (KI = 4.7–21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (KI = 24–50 nM). Compound 14 was the most potent inhibitor of hCA I (KI = 87 nM), hCA IX (KI = 4.7 nM) and hCA XII (KI = 0.96 nM), while 26 was the most effective inhibitor of hCA II (KI = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 26). The in vitro antitumor activity of compounds 10, 13, 14, 21, 22, 25, 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32–35 human tumor cell lines with GI50 in the range of 2.1–5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.

Inhibition of autophagy enhances apoptosis induced by proteasome inhibitor bortezomib in human glioblastoma U87 and U251 cells

Glioblastoma is the most aggressive cerebral gliomas. Despite advances in therapies, the prognosis is still very poor. Therefore, novel therapeutic strategies are required. As a proteasome inhibitor, bortezomib has shown its efficacy as an active antitumor agent against a variety of tumors. However, inhibition of proteasome activity leads to cell death and also induces cell autophagy, and due to the dual roles of autophagy in the survival and death of tumor cells, the effect of inhibition of autophagy on glioblastoma cells remains to be explored. We therefore assessed whether bortezomib is capable of inducing autophagy, and investigated the antitumor effect of bortezomib combined with autophagy inhibitors on human glioblastoma U251 and U87 cells. Cell viability was measured by MTT assay. The expressions of autophagy and apoptosis-related proteins were determined by Western blot analysis. U251 and U87 cells proliferation was inhibited in a dose-dependent manner. Both apoptosis and autophagy induced by bortezomib were observed in human glioblastoma U87 and U251 cells. However, when U251 and U87 cells were co-treated with bortezomib and autophagy inhibitors 3-MA or Atg7 siRNA, the autophagy inhibitors blocked the autophagy in the cells and resulted in a further inhibition of cell proliferation and a further increase in cell apoptosis as compared with that treated with bortezomib alone. These findings indicated that combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment.

The apoptosis of non-small cell lung cancer induced by cisplatin through modulation of STIM1

Cis-diamminedichloroplatinum (II) (cisplatin) is one of the most active antitumor agents used in human chemotherapy of non-small cell lung cancer. Cisplatin forms crosslinked DNA adducts and its cytotoxicity has been shown to be mediated by propagation of DNA damage recognition signals to downstream pathways prompting apoptosis. The steps involved in the process include changes in Ca(2+) signaling with dysregulated tumor cell turn-over. Stromal interaction molecules 1 (STIM1), as one of the most potent tumor suppressor genes, are identified as the endoplasmic-reticulum (ER) Ca(2+) sensor controlling store-operated Ca(2+) entry (SOCE) in non-excitable cells, which is main pathway to extracellular Ca(2+) influx. Its role in STIM1 cisplatin-induced apoptosis of non-small cell lung cancer was the focus of study with focus on SOCE inhibitors 2-APB- and SKF96365-cisplatin-induced apoptosis in the non-small cell lung cancer (NSCLC) cell lines A549 and H460. In this experimental model, cisplatin-induced apoptosis and decreased concentration of intracellular Ca(2+) was demonstrated. The expression of STIM1 was significantly higher in carcinoma tissue than in the adjacent non-neoplastic lung tissue. These findings support the conclusion that STIM1 may play an important role in the development of NSCLC which makes drugs that repress the expression of STIM1 to be a potential target for lung cancer therapy.

Garcinia Xanthones as Orally Active Antitumor Agents

Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural-product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D₇.₄, aqueous solubility, and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, two compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.

Are platinum agents, paclitaxel and irinotecan effective for clear cell carcinoma of the ovary? DNA damage detected with γH2AX induced by anticancer agents

ObjectivesDifferences in the incidences and types of DNA damage induced by antitumor agents for clear cell carcinoma (CCC) were determined in 2 ovarian CCC cell lines using γH2AX.Material and methodsThe antitumor activity of anticancer agents, CDDP, CBDCA, PTX and SN-38, was examined using ovarian clear cell carcinoma cultured cell lines (OVISE and RMG-I). After culture, each cell line was treated with each anticancer agent, the cells were collected, fixed, and then reacted with the anti-γH2AX antibody. γH2AX and nuclear DNA were then simultaneously detected by flow cytometry using FITC and propidium iodide, respectively, to determine γH2AX in each cell cycle phase.ResultsAfter administration of CDDP, DNA damage was frequent in S-phase cells, while cell-cycle arrest occurred in the G1 and G2/M phases and γH2AX did not increase in CDDP-resistant cells. Sensitivities to CDDP and CBDCA differed between the two cell lines. The antitumor effect of PTX is induced by G2/M arrest, and combination treatment with CBDCA, inducing DNA damage in G2/M-phase cells, might be effective.ConclusionsThis is the first study in Japan to evaluate the antitumor activity of anticancer agents by focusing on the relationship between the cell cycle and DNA damage using γH2AX as an indicator. The immunocytochemical method used in this study detects γH2AX, which indicates DNA damage even at very low concentrations and with high sensitivity. Therefore, a promising method of easily and rapidly identifying agents potentially effective against CCC.

The effect of light on gene expression and podophyllotoxin biosynthesis in Linum album cell culture

Podophyllotoxin (PTOX) is a naturally occurring phenolic compound isolated as an active anti-tumor agent. The stimulatory influence of light on the formation of phenolic compounds has been reported, but the molecular mechanism underlying the effect of light on the expression of genes involved in phenolic biosynthesis, especially of lignans, is still not fully understood. A series of experiments was carried out using ordinary fluorescent lamps to study the influence of light irradiation on growth and PTOX accumulation in Linum album cell cultures by varying the type of light and periods of exposure. The biosynthesis of PTOX was variably affected according to the quality of light. The enhancing effects of red light on PTOX production was correlated with increased activities of the enzyme phenylalanine ammonia-lyase (PAL), and the expression of some key genes involved in the biosynthesis of this compound, including the PAL gene itself and the cinnamoyl-CoA reductase (CCR) gene. Blue light was found to have similar effects but mainly on the expression level of CCR and pinoresinol lariciresinol reductase (PLR) genes.

Abstract 3733: Combined effect of linalool as component of Humulus lupulus on doxorubicin-induced antitumor activity

Abstract [Purpose] Cancer chemotherapy has been applied to advanced tumors and intractable tumors, playing an important role in their treatments. However, there are many problems including the appearance of adverse reactions and acquirement of drug resistance. The increased numbers of medications resulted in a decreased quality of life for the patients. However, food and food components can be used to increase the activity of antitumor agents without increasing the number of medicines. In this study, the effects of some components in Humulus lupulus (Hop) were examined on the doxorubicin (DOX) induced antitumor activity in vitro and in vivo. [Methods] The effects of Hop components (linalool, myrcene, α-humulene, α-caryophyllene) on DOX permeability and DOX cytotoxicity in P388 leukemia cells in vitro were examined. P388 leukemia cells (5 x 105 cells per animal) were transplanted onto the backs of BDF1 mice, and DOX (2.0mg/kg/day x 4 days, i.p.) and linalool (1.0mg/kg/day x 4 days, p.o.) were administered. The solid tumor and normal tissues were removed and measured DOX concentrations in each tissue. [Results and Discussion] In vitro, myrcene, α-humulene and α-caryophyllene did not have beneficial effects on DOX permeability in tumor cells. In contrast, the addition of linalool was shown to significantly promote on DOX influx and increased DOX concentration in tumor cells. The combination of DOX with linalool (0.1 μM) showed 3.5-fold (P<0.05) cytotoxicity, compared to treatment with DOX alone. Therefore, the combined linalool with DOX enhanced DOX cytotoxicity by the increase of DOX concentration in tumor cells. In vivo, the tumor weight in the DOX alone group decreased to 77% of the control level, whereas the combination of linalool with DOX decreased the tumor weight by 53% (P<0.05) of that in DOX alone group. In the tumor, the DOX concentration in the linalool combined group increased by 1.8-fold (P<0.05) compared to DOX alone group. In the normal tissue, the DOX concentration after combined linalool and DOX treatment tended to decrease. In particular, the DOX concentration in the heart decreased by 49% (P<0.05) of that in DOX alone group, expecting that linalool may decrease DOX-induced cardiotoxicity. Thus, the combination of linalool with DOX increased DOX concentration in the tumor, consequently enhanced antitumor activity of DOX. In conclusion, linalool is expected effectiveness as DOX modulator. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3733. doi:1538-7445.AM2012-3733

Artificial Chromosomes to Explore and to Exploit Biosynthetic Capabilities of Actinomycetes

Actinomycetes are an important source of biologically active compounds, like antibiotics, antitumor agents, and immunosuppressors. Genome sequencing is revealing that this class of microorganisms has larger genomes relative to other bacteria and uses a considerable fraction of its coding capacity (5–10%) for the production of mostly cryptic secondary metabolites. To access actinomycetes biosynthetic capabilities or to improve the pharmacokinetic properties and production yields of these chemically complex compounds, genetic manipulation of the producer strains can be performed. Heterologous expression in amenable hosts can be useful to exploit and to explore the genetic potential of actinomycetes and not cultivable but interesting bacteria. Artificial chromosomes that can be stably integrated into the Streptomyces genome were constructed and demonstrated to be effective for transferring entire biosynthetic gene clusters from intractable actinomycetes into more suitable hosts. In this paper, the construction of several shuttle Escherichia coli-Streptomyces artificial chromosomes is discussed together with old and new strategies applied to improve heterologous production of secondary metabolites.

Abstract A106: Investigation of 5-fluorodeoxycytidine with tetrahydrouracil as a demethylation regimen in solid tumors.

Abstract Methylation-induced silencing of gene promoters is widely documented in numerous cancer types, and the anti-tumor activity of agents that target this phenomenon has established DNA methyltransferase (DNMT1) as a valid drug target. We have investigated the combination of 5-fluorodeoxycytidine with Tetrahydrouridine (FdCyd + THU) in vitro and in vivo using continuous exposures up to 12 weeks. Supplementation of the medium with Deoxythymidine (10 μM) was required to prevent FdCyd cytotoxicity and allow sufficient time for demethylation to occur. Decitabine was used as the positive control throughout the evaluation. The bladder cancer line EJ6 was sensitive to FdCyd + THU, as evidenced by an increase in cell doubling time, a decrease in LINE1 methylation, and an initial decrease in total DNMT1 concentrations, determined with a newly-developed, quantitative two-site immunoassay. The triple negative breast cancer line MDA-MB-231 was resistant to the regimen, as assessed by all three criteria. The mechanism of this combination regimen in tumor cells isolated from paracentesis specimens from patients enrolled on an NCI-supported Phase 1 clinical trial of FdCyd + THU; and was confirmed by finding changes in both DNMT1 levels and LINE1 methylation. Upregulation of expression of p16 (INK4a), but not GSTP1 or RASSF1, was observed in EJ6 cells following FdCyd + THU by Western blotting. An immunofluorescence assay for p16 expression in circulating tumor cells (CTCs) has been developed and implemented in the Phase 1 trial. The ongoing Phase 2 trial of this regimen will include measurements of DNMT1 and LINE1 methylation in tumor biopsies and p16 in CTCs to directly assess drug effect on the DNMT1 target. This Research has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and NCI RAID Project #266 Grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A106.

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.

Abstract 3941: Amplifications of drug target genes in gastric cancer: Potential clinical implications

Abstract Background: The treatment of advanced gastric cancer remains a challenge for the clinical oncologist. Once distant metastases are present, median survival is around one year with the most active chemotherapeutic regimen. Besides the recent approval of trastuzumab in combination with chemotherapy, thus far no other molecular targeted agents have been approved for the treatment of this disease. There is an urgent need to improve selection of effective treatment for individual patients. A potentially promising approach for selecting active antitumor agents in individual patients could be the evaluation of tumor DNA for amplifications of genes coding for drug targets. Material and Methods: 183 primary gastric adenocarcinomas were analyzed by genome wide array Comparative Genomic Hybridization (arrayCGH) using microarrays consisting of 5000 BAC clones. High level amplifications were defined as a minimum of 2 consecutive clones showing a log2 tumor to normal ratio of > 1. Amplification frequencies for each BAC clone were calculated among the 183 tumors, and genes located within the amplicons were identified by using the RefSeq genes in the UCSC genome browser, version hg16/NCBI34. Drug target genes were selected with Ingenuity Pathway Analysis (IPA) and the Pharmacogenomics Knowledge Base (PharmGKB). Genes amplified in at least 4 patients (2%) were classified according to the mechanism of action of the drug interacting with this specific gene. Results: In 183 gastric cancers a mean number of 2.0 amplifications per tumor (range 0-21) was found. 167 genes out of more than 6000 at these loci were annotated as drug target genes by IPA, with 30 genes having an amplification frequency of at least 4 (2%). Most frequently amplified regions were located on chromosome 6, 8, 11, 16, 17 and 20. Genes for molecular targeting agents included VEGFA (6.5%), ERBB2 (6%), HSP90AB1 (5.5%) and EGFR (3.8%). Interestingly, also genes for non-anticancer agents, including HRH3 (10.4 %) and RARA (4.9%), and potential therapeutic targets such as TNFRSF4B (7.1%) were found. Conclusion: ArrayCGH analysis of a large series of gastric tumors revealed many non-randomly amplified gene loci, including substrates for targeted agents with potential antitumor activity in advanced gastric cancer. Moreover, targets of agents without established anticancer activity were identified as well. Our results provide a molecular rationale for the investigation of new treatment strategies in advanced gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3941. doi:10.1158/1538-7445.AM2011-3941

DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057

The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. SG2000 is a propyldioxy linked PBD dimer which binds sequence selectively in the minor groove of DNA forming DNA interstrand and intrastrand cross-linked adducts, and also mono-adducts depending on sequence. SG2057 is the corresponding dimer containing a pentyldioxy linkage. SG2057 has multilog differential in vitro cytotoxicity against a panel of human tumour cell lines with a mean GI(50) of 212 pM. The agent is highly efficient at producing DNA interstrand cross-links in cells which form rapidly and persist over a 48h period. Significant antitumor activity was demonstrated in several human tumor xenograft models. Cures were obtained in a LOX-IMVI melanoma model following a single administration and dose-dependent activity, including regression responses, observed in SKOV-3 ovarian and HL-60 promyelocytic leukemia models following repeat dose schedules. In the advanced stage LS174T model, SG2057 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development.

A Human Head and Neck Squamous Cell Carcinoma Cell Line with Acquiredcis-Diamminedichloroplatinum-Resistance Shows Remarkable Upregulation of BRCA1 and Hypersensitivity to Taxane

Recently, an inverse relationship between resistance to platinum-based chemotherapeutic agents and taxanes has been implicated in breast and ovarian cancers, and a possible pivotal role for BRCA1 has also been suggested. Because cis-diamminedichloroplatinum (CDDP) and taxanes are the most active antitumor agents against head and neck squamous cell carcinoma (HNSCC), we analyzed the sensitivity of nine HNSCC cell lines and their previously established derived CDDP-resistant cell lines to two representative taxanes: docetaxel and paclitaxel. None of the nine original cell lines showed any cross resistance between CDDP and taxanes, but one of the CDDP-resistant cell lines, RPMI2650CR, demonstrated hypersensitivity to both taxanes when compared to the parental cell line, RPMI2650. Furthermore, RPMI2650CR exhibited increased expression of BRCA1. These data suggest that (i) taxanes are a good candidate for a second-line therapeutic drug for HNSCC patients with acquired CDDP resistance and (ii) BRCA1 can be a candidate marker for predicting an inverse CDDP/taxane sensitivity phenotype in HNSCC.

Abstract A67: Phase IIA trial testing erlotinib as an intervention against intraductal papillary mucinous neoplasms

Abstract Intraductal papillary mucinous neoplasms (IPMNs) account for about 7% of clinically diagnosed pancreatic neoplasm and up to 50% of all incidentally detected pancreatic cysts. Described by Oshi et al in 1982, the incidence of these mucin-producing epithelial tumors of the exocrine pancreas has been increasing. Furthermore, IPMNs are thought to be direct precursors of pancreatic ductal carcinoma (PDA), which is among the most lethal human cancers. Many of the IPMNs are detected occur in nonsurgical candidates. Those surgically resected, a significant proportion develops PDA in the pancreatic remnant and die of disseminated disease. There is currently no chemotherapy specifically approved for treating IPMNs. Erlotinib (Tarceva, OSI-774) is an anti epidermal growth factor receptor (EGFR) orally active antitumor agent for treatment of solid tumors that is used in combination with chemotherapy to treat pancreatic adenocarcinoma. A single arm, presurgical phase IIa trial using 100mg erlotinib in IPMNs patients (7-28 days prior to surgery) was conducted. Pre and post-erlotinib IPMN tissues were compared for a reduction in the EGF regulated biomarker Mucin 5AC (MUC 5AC) as the primary outcome. Secondary outcomes included clinical regression of IPMNs and quantification of the concentration of erlotinib in pancreatic tissue. Six IPMN patients were enrolled and pancreatic surgical specimens consistently showed decreased MUC5AC with erlotinib treatment. Additionally, one patient had a clinical complete response by CT criteria. No unanticipated safety issues were observed in trial participants. Overall, these preliminary results suggest erlotinib and other EGFR antagonists should be examined further for anti-IPMN activity. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A67.

DNA Topoisomerase II Enzymes as Molecular Targets for Cancer Chemotherapy

DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase IIα and IIβ. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These post-translational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.

BPR0C261 is a novel orally active antitumor agent with antimitotic and anti‐angiogenic activities

BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G(2)/M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug-resistant phenotype. In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary-like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC(50) values against the endothelial cell growths were approximately 10-fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco-2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose-dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin-binding antitumor agent with antimitotic, apoptosis-inducing, and vasculature disrupting activities.

Podophyllotoxin: Current approaches to its biotechnological production and future challenges

AbstractMany plant‐derived agents are being used to treat cancer, including taxol, vinblastine, vincristine, or camptothecin and podophyllotoxin derivatives, among others. Plant biotechnology can provide a new tool for the production of anticancer agents but in spite of considerable efforts to produce vinblastine and vincristine in cell cultures and knowledge of the biosynthetic pathway of Catharanthus roseus alkaloids, the biotechnological production of taxol has only been achieved at an industrial level by companies such as Phyton Biotech and Cytoclonal Pharmaceutics. Podophyllotoxin was isolated as the active antitumor agent from the roots of Podophyllum species and more recently from the genus Linum and others. Etoposide, teniposide, and etophos are semi‐synthetic derivatives of podophyllotoxin and are used in the treatment of cancer. Biotechnological approaches, including the use of cell cultures, biotransformation, or metabolic engineering techniques to manipulate the biosynthetic pathway, represent an alternative for the production of podophyllotoxin and are discussed in this review.

Amphiphilic hyper-branched co-polymer nanoparticles for the controlled delivery of anti-tumor agents

In this investigation, we have designed and synthesized an amphiphilic co-polymer with hyper-branched poly(amine-ester) and polylactide (HPAE-co-PLA) to generate nanoparticles (NPs). These have been used to encapsulate a highly active hydrophobic anti-tumor agent, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT). Encapsulation in NPs was done in an effort to increase the anti-tumor activity of this agent by facilitating its delivery to tumor cells. We have also examined and optimized the formulation parameters of the NPs that alter their drug-loading capacity and their physical, chemical and biological properties. The resulting NPs exhibited high Bp4eT-loading capacity and substantial stability in aqueous solution. In vitro drug release studies demonstrated a controlled drug release profile with increased release at acidic pH. Anti-tumor proliferation assays showed that both free drug and drug-encapsulated NPs markedly inhibited tumor cell proliferation in a time- and concentration-dependent manner. Direct microscopic observation revealed that the fluorescent NPs were taken up by cells and localized, in part, in organelles consistent with lysosomes. These results demonstrate a feasible application of the amphiphilic hyper-branched co-polymer, HPAE-co-PLA, as nanocarriers for intracellular delivery of potent anti-tumor agents.

Study of the efficacy of 5 ALA-mediated photodynamic therapy on human larynx squamous cell carcinoma (Hep2c) cell line

5-aminolevulanic acid (ALA), a precursor of Protoporphyrin IX, was evaluated as an inducer of photodamage on Hep2c, human larynx squamous cell carcinoma, cell line. Porphyrins are used as active cytotoxic antitumor agents in photodynamic therapy (PDT). The present study evaluates the effects of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) using human larynx cells as experimental model. Hep2c cell line was irradiated with red light (a diode laser, λ = 635 nm). The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the cellular viability of Hep2c cells were studied. The optimal uptake of photosensitizer ALA in Hep-2c cells was investigated by means of spectrometric measurement. Cells viability was determined by means of neutral red assay (NR). It was observed that sensitizer or light doses have no significant effect on cells viability when studied independently. The spectrometric measurements showed that the maximal cellular uptake of 5-ALA occurred after 7 h in vitro incubation. The photocytotoxic assay showed that light dose of 85 J/cm2 gives effective PDT outcome for Hep2c cell line incubated with 55 μg/ml of 5-ALA with a conclusion that Hep2c cell line is sensitive to ALA-mediated PDT.

Pharmacoeconomic Aspects of FOLFIRI or FOLFOX Regimens Administered with a Fully Ambulatory Pump Compared to the Day Hospital Setting

The social cost of management of patients suffering from colorectal cancer has been growing dramatically in the last decade due to the high number of active antitumor agents and to the increased incidence of the tumor in western countries. The aim of the study was to explore from a pharmacoeconomic point of view a different way to administer the two most common regimens in this patient setting. This was a cost-minimization study. Data were extracted from hospital registries and dedicated offices. The traditional setting (day hospital inpatient setting) and a fully ambulatory setting (CIP pump) were considered and compared. The CIP system resulted in higher direct costs than the day hospital setting (444.70 versus 159.00 euro/cycle). However, traditional infusion resulted in longer nursing care, with an increase in nursing costs of more than 100.00 euro/cycle. Moreover, the inpatient setting obliged patients to stay in the hospital as much as ten times longer than with the CIP system. This meant that with the same time span and the same resources, the CIP pump permitted treatment of at least five times more patients than the traditional setting. Thus, a threshold of 52.00 euro per patient for general hospital costs (ordinary and extraordinary maintenance of buildings, power supply, and housekeeping) was identified to discriminate whether the CIP pump is cost-saving or not. Administration of the FOLFIRI or FOLFOX regimen in a traditional day hospital setting was less costly when considering the direct costs. However, a fully ambulatory pump permitted to better employ hospital resources and could permit cost-saving in those units in which more than five patients per day are treated and global costs are higher than 52.00 euro per patient.