Doses Of Anticancer Drugs Research Articles

Growth Hormone Receptor Knockdown Sensitizes Human Melanoma Cells to Chemotherapy by Attenuating Expression of ABC Drug Efflux Pumps.

Melanoma remains one of the most therapy-resistant forms of human cancer despite recent introductions of highly efficacious targeted therapies. The intrinsic therapy resistance of human melanoma is largely due to abundant expression of a repertoire of xenobiotic efflux pumps of the ATP-binding cassette (ABC) transporter family. Here, we report that GH action is a key mediator of chemotherapeutic resistance in human melanoma cells. We investigated multiple ABC efflux pumps (ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, ABCG1, and ABCG2) reportedly associated with melanoma drug resistance in different human melanoma cells and tested the efficacy of five different anti-cancer compounds (cisplatin, doxorubicin, oridonin, paclitaxel, vemurafenib) with decreased GH action. We found that GH treatment of human melanoma cells upregulates expression of multiple ABC transporters and increases the EC50 of melanoma drug vemurafenib. Also, vemurafenib-resistant melanoma cells had upregulated levels of GH receptor (GHR) expression as well as ABC efflux pumps. GHR knockdown (KD) using siRNA in human melanoma cells treated with sub-EC50 doses of anti-tumor compounds resulted in significantly increased drug retention, decreased cell proliferation and increased drug efficacy, compared to mock-transfected controls. Our set of findings identify an unknown mechanism of GH regulation in mediating melanoma drug resistance and validates GHR as a unique therapeutic target for sensitizing highly therapy-resistant human melanoma cells to lower doses of anti-cancer drugs.

Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report

BackgroundThe safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown.Case presentationWe describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen.ConclusionsBecause of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells.

Limited information is currently available on how to apply epigenetic modifiers to current colorectal cancer (CRC) chemotherapy. The purpose of this study is to clarify the schedule-dependent effects of combined treatment with conventional anticancer drugs and epigenetic modifiers in human CRC cells. Cytotoxicity in 4 CRC cell lines (SW480, HT29, SW48, and HCT116) was measured using the WST-8 assay. As epigenetic modifiers, 3 DNA methyltransferase (DNMT) inhibitors such as decitabine (DAC), azacytidine (AC), and zebularine (Zeb), and 3 histone deacetylase (HDAC) inhibitors including trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid (VPA) were used. Combination effects were analyzed by the isobologram method. SW480 cells showed the lowest sensitivity to the anticancer drugs 5-fluorouracil, SN-38 (the active form of irinotecan), and oxaliplatin. In SW480 cells, epigenetic modifiers other than VPA showed the most significant synergistic effects when used before anticancer drugs, while VPA showed synergistic effects in co- or post-treatment. In the 3 other CRC cells, synergistic effects were less frequent and weaker. The dose of anticancer drugs may be reduced by combining epigenetic modifiers in SW480 cells, which are less sensitive to anticancer drugs, unlike the more sensitive HT29, SW48, and HCT116 cell lines. These results provide useful information for understanding how to incorporate epigenetic modifiers into current CRC chemotherapy.

Derivation of a Unique Body Surface Area (Bsa) Formula for Calculation of Relatively Safe Doses of Dog and Human Anticancer Drugs

The safety of anticancer dosing has become a serious concern due to high incidence of life-threatening toxicity signs. More so, dogs are used as models of research for human cancers. In view of these a uniform body surface area (BSA) formula has been derived for human and dog with a view to having low, safe, effective therapeutic doses of anticancers. The derived formula (BSA=BW0.528 × H0.528 × K) was used to calculate BSAs of greyhound, toy, companion, terrier, hunting and working dogs and yielded low effective therapeutic doses of dacarbazine, asparaginase, streptozotocin, dactinomycin, epirubicine and prednisolone. Hunting and working dogs have high body weight, BMI and BSAs similar to that of human and may be prone to obesity and obesity associated diseases. Whereas BSAs and doses of anticancer agents of light and relatively tall dogs are relatively higher in comparison with that of short and light dogs. Greyhounds have higher BSA in comparison with toys, companions and terriers. Working breeds of dog such as Treeing Walker Coon haired (65.0 kg), Great Swiss mountain dog (59.0 kg), longhaired St. Bernard (55.0 kg), French Mastiff (50.0 kg) and female Komondor (59.0 kg) have same BSA values with humans weighing 51.3, 46.7, 44.8, 44.0 and 43.0 kg, respectively. Calculated common exponent (0.528) for body weight and height may be the common relationship between basal metabolism of dog and human.

Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes but not Normal Lymphocytes

The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein-carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects.

Inhibition of the Pentose-phosphate Pathway Selectively Sensitizes Leukemia Lymphocytes to Chemotherapeutics by ROS-independent Mechanism.

The aim of the present study was to investigate: (i) the possibility of sensitizing leukemia lymphocytes to anticancer drugs by inhibiting pentose-phosphate pathway using 6-aminonicotinamide (6-ANA); (ii) to find combinations with synergistic cytotoxic effect on leukemia lymphocytes and to investigate their cytotoxicity towards normal lymphocytes; (iii) and to clarify the role of reactive oxygen species (ROS) in the induction of apoptosis by those combinations. The study covers 15 anticancer drugs - conventional and new-generation. The experiments were performed on Jurkat leukemia cell line and normal lymphocytes, isolated from clinically healthy blood donors. Four parameters were analyzed simultaneously in both cell suspensions treated by drug or 6-ANA (separately, and in combination): cell viability, induction of apoptosis, level of ROS, and level of protein-carbonyl products. Most combinations of drug plus 6-ANA were characterized by synergistic cytotoxic effects on Jurkat cells. The synergism increased with increasing incubation time. Upon combination of 6-ANA with conventional chemotherapeutic (e.g. doxorubicin), synergistic cytotoxic effects were also detected in normal lymphocytes. In both cell types, the cytotoxicity of the combination of doxorubicin plus 6-ANA was accompanied by increased induction of apoptosis, but by a slight reduction of ROS and protein-carbonyl products compared to cells treated with doxorubicin only. Upon combination of 6-ANA with new-generation anticancer drugs (e.g. everolimus or barasertib), the synergistic cytotoxic effect on leukemia lymphocytes was also accompanied by very strong induction of apoptosis through ROS-independent mechanism(s). Neither of these combinations exhibited any cytotoxicity towards normal lymphocytes. The data suggest that 6-ANA could be used as a supplementary component in anticancer chemotherapy, and would allows therapeutic doses of anticancer drugs to be reduced, thereby minimizing their side-effects.

Preparation, characterization and in vitro release kinetics of polyaspartamide-based conjugates containing antimalarial and anticancer agents for combination therapy

Malaria is treated by combination of two drugs in order to overcome drug resistance. Antimalarials have been found to be more effective by combining them with low doses of anticancer drugs. Polymer-drug conjugates containing aminoquinoline and ferrocene derivatives were prepared from polyaspartamides polymers. These conjugates physicochemical properties were characterized. FTIR and 1H NMR confirmed the successful incorporation of aminoquinoline and ferrocene analogues onto the polyaspartamides polymers. The XRD thermograms indicated the amorphous nature of the polymer-drug conjugates and the successful incorporation of the drugs onto the polymer carriers. It further indicated the absence of free 4-aminoquinoline and ferrocene analogues. The rate of release of the bioactive drugs was slow at pH 7.4 and fast at pH 1.2. The release mechanism of ferrocene analogue from the carrier was super case II whereas the release mechanism of the 4-aminoquinoline from the carrier was a case II. Zero order release mechanism dominated the first 24 h. The release mechanisms of the bioactive drugs and physico-chemical properties from the polyaspartamide-based carriers suggested that they are potential drug delivery which can be used to overcome drug resistance that is common with the presently used antimalarials.

Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents.

First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA's operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core-shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response.

Nano-structures mediated co-delivery of therapeutic agents for glioblastoma treatment: A review

Glioblastoma is a malignant brain tumor and leads to death in most patients. Chemotherapy is a common method for brain cancer in clinics. However, the recent advancements in the chemotherapy of brain tumors have not been efficient enough. With the advancement of nanotechnology, the used drugs can enhance chemotherapy efficiency and increase the access to brain cancers. Combination of therapeutic agents has been recently attracted great attention for glioblastoma chemotherapy. One of the early benefits of combination therapies is the high potential to provide synergistic effects and decrease adverse side effects associated with high doses of single anticancer drugs. Therefore, brain tumor treatments with combination drugs can be considered as a crucial approach for avoiding tumor growth. This review investigates current progress in nano-mediated co-delivery of therapeutic agents with focus on glioblastoma chemotherapy prognosis.

Renal insufficiency and cancer treatments

Renal insufficiency has been shown to be highly prevalent in patients with cancer. This renal insufficiency has been reported to be associated with reduced overall survival and increased cancer-related mortality. Therefore, it is important to screen patients with cancer for renal insufficiency, using an adequate and reliable method of estimation of the renal function. Renal insufficiency may influence 1 or several of the 4 pharmacokinetic phases (absorption, distribution, metabolism, elimination/excretion), potentially resulting in marked modifications of the pharmacokinetic profile of a drug in patients with renal insufficiency. Consequently, it is potentially necessary to adjust the dosage of anticancer drugs in case of renal insufficiency in order to avoid drug accumulation and in order to reduce overdosage-related side effects. This dosage adjustment of anticancer drugs should be performed according to the level of renal function and with an appropriate and validated method. It is not always easy to find clear information on anticancer drug handling in these patients. However, several guidelines, publications and handbooks are available on how to adjust anticancer drug dosages in patients with renal insufficiency and will help practitioners to manage anticancer drugs in such patients.

Cutaneous toxic effects of targeted therapy: clinical manifestations and correction

Targeted therapy used in oncology today is the most effective, but frequent cutaneous side effects force to reduce dose or interrupt treatment, significantly reducing the anti-tumor effect. The data on the pathogenesis of toxic skin reactions and the most frequent clinical manifestations (papular-pustular reaction, hand-foot syndrome) according to various studies are presented. The basic principles of correction are described. Examples of anticancer drug doses correlation and severity of skin reactions are presented.

Incidence, severity and factors associated with diarrhoea in phase I oncology studies: experience of 1002 consecutive cases.

2568Background: Diarrhea is a common toxicity related to cancer treatment. Diarrhea occurs at different degrees of severity both within and outside the dose limiting toxicity window, influencing the dose and schedule of novel anticancer drugs. We aimed to assess the incidence, severity and factors predisposing to diarrhea in patients (pts) enrolled in phase I studies. Methods: This is a retrospective study of 1002 separate phase I trial pt-cases treated at the Royal Marsden Hospital Drug Development Unit between January 2010 and December 2014. Data were collected from our electronic records for consecutive pts participating in 80 different phase I trials. Results: The incidence of diarrhea was 32.1%. Grade 1-5 diarrhea was reported in 21.9%, 6.3%, 3.1%, 0.1% and 0.1% pt-cases respectively. 69.5% episodes of diarrhea were reported as drug related. 5.6% of pts had a specific trial intervention due to diarrhea such as dose interruption or withdrawal from study. Time on study was not significantly different i...

Current approach and recommendations for standardized dosing of anticancer drugs in infants.

10546Background: In children, most anticancer drugs are dosed based on body surface area (BSA), but BSA dosing is often too toxic for infants. This led to empirical dose modifications in infants, u...

Cost avoidance from dose rounding biologic and cytotoxic antineoplastics.

Background To reduce product wastage, our institution allows automatic dose rounding of biologic and cytotoxic anticancer agents. The purpose of this project was to determine the actual annual cost avoidance due to pharmacist-managed automatic dose rounding of anticancer treatments. Methods Financial impact was assessed within the context of our departmental standard work which supports automatic dose rounding of biologic anticancer agents (±10%) and cytotoxic anticancer agents (±5%) to the nearest vial size for body surface area- or weight-based doses. Exclusions to automatic dose rounding include multiple dose vial products, pediatric orders, clinical trial drugs, and parenteral busulfan. The amount of cost avoidance for each rounded dose was determined using the product acquisition cost of the smallest available product amount. Data were collected from anticancer treatment orders for the fiscal year 1 July 2013 to 30 June 2014. Results A total of 6216 doses of anticancer drugs were checked for dose rounding during the period of data collection. Almost $200,000 in product acquisition cost was avoided with pharmacist-managed automatic dose rounding. Six different biologic products accounted for approximately 7% of the total doses analyzed and 78% of the cost avoidance. Fifteen drugs comprised the array of cytotoxic agents rounded. Approximately, 37% and 4% of the biologic and cytotoxic doses were rounded up to the vial size. Conclusion Routine dose rounding of biologic anticancer agents (±10%) and cytotoxic products (±5%) achieved cost avoidance through reduction of drug wastage at our institution.

Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens.

PurposeSelection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms’ tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs.MethodsPlasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity.ResultsTreatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01–0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing.ConclusionsThe current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients.

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis.

IntroductionIsolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US).MethodsRetrospective, observational study, using administrative claims data from the MarketScan® databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed.ResultsOne hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (±SD) length of hospital stay was 5.6 (±3.5) days and the mean (±SD) cost was US$36,758 (±27,124) per ILP/ILI procedure.ConclusionsIsolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma.FundingThis study was funded by Amgen, Inc.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0283-z) contains supplementary material, which is available to authorized users.

Targeting protein kinases to reverse multidrug resistance in sarcoma.

Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.

Abstract A2-27: Effects of C-Phycocyanin in combination with anticancer drugs in lung cancer implanted mice

Abstract The C-Phycocyanin (C-PC) is a pigmented phycobiliprotein that is produced by the blue-green algae (cyanobacterium) named Spirulina platensis and Limnothrix sp. For the first time we have tested the anticancer properties of C-PC from the cyanobacterial isolate Limnothrix sp., that is found in Florida's Everglades, using cancer cells and xenograft tumor model. Our preliminary studies confirm that C-PC from Limnothrix have antiproliferative activity against LNCaP prostate cancer cells. However, as expected the required concentration of C-PC for anticancer activity is well above the usual doses of anticancer drugs normally used. Therefore, we speculated that C-PC could potentiate the anticancer effects of certain therapeutic agents when used in combination treatment. Initially the cytotoxic effects of C-PC and Topotecan (TPT) were confirmed using cell viability assays in A-549 lung cancer cells. Also, it was determined that C-PC treatment could significantly down regulate the levels of Bcl-2, an anti-apoptotic protein, to induce apoptosis. Furthermore, our in vivo experiments confirmed the efficacy of C-PC in potentiating the anticancer effects of Taxol, Topotecan and Cisplatin in athymic nude mice that were sub-cutaneously implanted with the xenograft tumors established from A549 lung cancer cells. During the treatment period the experimental mice had free access to C-PC dissolved in drinking water at a dose of 100 mg/Kg body weight. All the other anticancer drugs were given as intraperitoneal (i.p.) injections at a dose of 1.0 mg/kg body weight twice a week for a period of 60 days. Tumor growth was assessed once in every two weeks using caliper measurements. At the end of the treatment period the level of lung tumor biomarker CYFRA 21-1 in serum was analyzed. As a result of the treatment, the tumor growth was found to be 54%, 46% and 33% less in Taxol; TPT and Cisplatin treated groups compared to the control group. Interestingly C-PC + Taxol combination showed 75% inhibition while C-PC + TPT showed 51% and C-PC + Cisplatin showed 40% inhibition of tumor growth. Thus, the mice treated with the C-PC + Taxol combination showed an additional 21% tumor growth inhibition when compared to group treated with Taxol alone. Furthermore, the decreased level of CYFRA 21-1in serum showed a good correlation with the inhibition of tumor growth in C-PC + Taxol treated animals. Results from our study confirm that C-PC from Limnothrix sp., can significantly enhance the anticancer activity of Taxol against the A549 lung tumor in athymic nude mice possibly by decreasing the levels of Bcl-2. (This project was supported by the PFRDG grant of NSU and grants from the James & Esther King Biomedical Research Program of the State of Florida and the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Sivanesan Dhandayuthapani, Miroslav Gantar, Appu Rathinavelu. Effects of C-Phycocyanin in combination with anticancer drugs in lung cancer implanted mice. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-27.

Personalizing chemotherapy dosing using pharmacological methods.

Given the toxic nature and narrow therapeutic index of traditional chemotherapeutics, better methods of dose and therapy selection are critical. Pharmacological methods, including pharmacogenomics and pharmacokinetics, offer a practical method to enrich drug exposure, reduce toxicity, and improve quality of life for patients. PubMed and key abstracts from the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR) were searched until July 2015 for clinical data relating to pharmacogenomic- and/or pharmacokinetic-guided dosing of anticancer drugs. Based on the results returned from a thorough search of the literature and the plausibility of utilizing pharmacogenomic and/or pharmacokinetic methods to personalize chemotherapy dosing, we identified several chemotherapeutic agents with the potential for therapy individualization. We highlight the available data, clinical validity, and utility of using pharmacogenomics to personalize therapy for tamoxifen, 5-fluorouracil, mercaptopurine, and irinotecan, in addition to using pharmacokinetics to personalize dosing for 5-fluorouracil, busulfan, methotrexate, taxanes, and topotecan. A concerted effort should be made by researchers to further elucidate the role of pharmacological methods in personalizing chemotherapy dosing to optimize the risk-benefit profile. Clinicians should be aware of the clinical validity, utility, and availability of pharmacogenomic- and pharmacokinetic-guided therapies in clinical practice, to ultimately allow optimal dosing for each and every cancer patient.

Abstract 290: In situ delivery and production of anti-HER2 scFv

Abstract Introduction: Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2), has become the main therapeutics for HER2-positive breast cancers. Recently, active scFvs (single-chain variable fragment) were produced and anti-tumor function like BITE (Bi-specific T cell engagers) has been added to improve the antitumor efficacy. On the one hand, the in situ delivery and continuous production of anti-cancer drugs at the tumor site will be required to evade adverse effects and elevate the dose of anti-cancer drugs in tumor tissues. We have established such in situ Delivery and continuous Production System (iDPS) with Bifidobacterium that can selectively target hypoxic microenvironment of solid cancer tissues. The purpose of the present study is to establish continuous production and secretion system for biologically active anti-HER2 scFv by Bifidobacterium. Materials and Methods: We constructed an expression vector of anti-HER2 scFv based on the cDNA sequence of anti-HER2 antibody for E. coli. The biological activity of the product was examined by ELISA, FACS, fluorescence-immunostaining and MTT assay for cell growth using differentially HER2-expressing human cell lines. Anti-tumor activity was assessed by intratumoral injection with the anti-HER2 scFv for tumors of a human breast cancer cell line transplanted into nude mice. We further modified the above vector for E. coli. to make a shuttle vector for Bifidobacterium. The binding activity of the product to HER2 was confirmed by ELISA and the primary structure was examined by LC-MS. Results: First, we succeeded in producing the recombinant scFv by E. coli, which showed specific binding to HER2. The anti-HER2 scFv inhibited the in vitro growth of several HER2-positive human cancer cell lines with the same efficiency as Trastuzumab. The intratumoral injection of the recombinant anti-HER2 scFv to transplanted human breast cancer tissues in nude mice showed a significant inhibition of the tumor growth. Next, to prepare iDPS of anti-HER2 scFv, we developed a recombinant Bifidobacterium longum to express and secrete anti-HER2 scFv, which was shown to bind to HER2 by ELISA, and its primary structure was confirmed to be the same as the recombinant anti-HER2 scFv produced by E. coli. Conclusion: We believe that iDPS for anti-cancer substances like anti-HER2 scFv can contribute to the reduction of adverse effects and a better-cost performance than current antibody medicines. Importantly, the upcoming study to modify anti-HER2 scFv to carry BITEs-like activity will be planned, which can provide much more therapeutic effects for not only breast cancers but also other cancers expressing HER2. Citation Format: Takeshi Kikuchi, Hitomi Shimizu, Yasuto Akiyama, Shun'ichiro Taniguchi. In situ delivery and production of anti-HER2 scFv. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 290. doi:10.1158/1538-7445.AM2015-290