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Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development worldwide, and Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat., Aims: This study aims at developing novel HDAC inhibitors bearing quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines., Methods: A series of novel N-hydroxyheptanamides incorporating 6-hydroxy-2 methylquinazolin-4(3H)-ones (14a-m) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2 (liver cancer), MCF-7 (breast cancer) and SKLu-1 (lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. ADME-T predictions for selected compounds were also performed to predict some important features contributing to the absorption profile of the present hydroxamic derivatives., Results: It was found that the N-hydroxyheptanamide 14i and 14j were the most potent, both in terms of HDAC inhibition and cytotoxicity. These compounds displayed up to 21-71-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in terms of cytotoxicity, and strong inhibition against the whole cell HDAC enzymes with IC 50 values of 7.07-9.24μM. Docking experiments on HDAC2 isozyme using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.02 to -11.23 kcal/mol) compared to SAHA (-7.4 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward breast cancer cells (MCF-7) than liver (HepG2), and lung (SKLu-1) cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Acute lymphoblastic leukemia (ALL) is a blood cancer that is characterized by the overproduction of lymphoblasts in the bone marrow. Treatment for pediatric ALL typically uses combination chemotherapy in phases, including a prolonged maintenance phase with oral methotrexate and 6-mercaptopurine, which often requires dose adjustment to balance side effects and efficacy. However, a major challenge confronting combination therapy for virtually every disease indication is the inability to pinpoint drug doses that are optimized for each patient, and the ability to adaptively and continuously optimize these doses to address comorbidities and other patient-specific physiological changes. To address this challenge, we developed a powerful digital health technology platform based on phenotypic personalized medicine (PPM). PPM identifies patient-specific maps that parabolically correlate drug inputs with phenotypic outputs. In a disease mechanism-independent fashion, we individualized drug ratios/dosages for two pediatric patients with standard-risk ALL in this study via PPM-mediated retrospective optimization. PPM optimization demonstrated that dynamically adjusted dosing of combination chemotherapy could enhance treatment outcomes while also substantially reducing the amount of chemotherapy administered. This may lead to more effective maintenance therapy, with the potential for shortening duration and reducing the risk of serious side effects.

Basal-like breast cancers are highly aggressive malignancies associated with very poor prognosis. Although these cancers may initially respond to first-line treatment, they become highly resistant to standard chemotherapy in the metastatic setting. Chemotherapy resistance in basal-like breast cancers is associated with highly selective overexpression of the homeobox transcription factor Engrailed 1 (EN1). Herein, we propose a novel therapeutic strategy using poly(glycidyl methacrylate) nanoparticles decorated with poly(acrylic acid) that enable dual delivery of docetaxel and interference peptides designed to block or inhibit EN1 (EN1-iPep). We demonstrate that EN1-iPep is highly selective in inducing apoptotic cell death in basal-like cancer cells with negligible effects in a non-neoplastic human mammary epithelial cell line. Furthermore, we show that treatment with EN1-iPep results in a highly synergistic pharmacological interaction with docetaxel in inhibiting cancer cell growth. The incorporation of these two agents in a single nanoformulation results in greater anticancer efficacy than current nanoparticle-based treatments used in the clinical setting.

Combination chemotherapy can mediate drug synergy to improve treatment efficacy against a broad spectrum of cancers. However, conventional multidrug regimens are often additively determined, which have long been believed to enable good cancer-killing efficiency but are insufficient to address the nonlinearity in dosing. Despite improved clinical outcomes by combination treatment, multi-objective combination optimization, which takes into account tumor heterogeneity and balance of efficacy and toxicity, remains challenging given the sheer magnitude of the combinatorial dosing space. To enhance the properties of the therapeutic agents, the field of nanomedicine has realized novel drug delivery platforms that can enhance therapeutic efficacy and safety. However, optimal combination design that incorporates nanomedicine agents still faces the same hurdles as unmodified drug administration. The work reported here applied a powerful phenotypically driven platform, termed feedback system control (FSC), that systematically and rapidly converges upon a combination consisting of three nanodiamond-modified drugs and one unmodified drug that is simultaneously optimized for efficacy against multiple breast cancer cell lines and safety against multiple control cell lines. Specifically, the therapeutic window achieved from an optimally efficacious and safe nanomedicine combination was markedly higher compared to that of an optimized unmodified drug combination and nanodiamond monotherapy or unmodified drug administration. The phenotypically driven foundation of FSC implementation does not require any cellular signaling pathway data and innately accounts for population heterogeneity and nonlinear biological processes. Therefore, FSC is a broadly applicable platform for both nanotechnology-modified and unmodified therapeutic optimizations that represent a promising path toward phenotypic personalized medicine.

The advent of cancer nanomedicine has forged new pathways for the enhanced imaging and treatment of a broad range of cancers using new classes of materials. Among the many platforms being developed for drug delivery and imaging, nanodiamonds (NDs) possess several important attributes that may be beneficial toward improving the efficacy and safety of cancer nanomedicine applications. These include the uniquely faceted surfaces of the ND particles that result in electrostatic properties that mediate enhanced interactions with water and loaded therapeutic compounds, scalable processing and synthesis parameters, versatility as platform carriers, and a spectrum of other characteristics. In addition, comprehensive in vitro and in vivo studies have demonstrated that NDs are well tolerated. This chapter will examine several recent studies that have harnessed the ND agent as a foundation for both systemic and localized drug delivery, as well as the marked improvements in magnetic resonance imaging efficiency that has been observed following ND-contrast agent conjugation. In addition, insight into the important steps toward bringing the ND translational pathway to the clinic will be discussed.

Self-assembled nanodiamond-lipid hybrid particles (NDLPs) harness the potent interaction between the nanodiamond (ND)-surface and small molecules, while providing a mechanism for cell-targeted imaging and therapy of triple negative breast cancers. Epidermal growth factor receptor-targeted NDLPs are highly biocompatible particles that provide cell-specific imaging, promote tumor retention of ND-complexes, prevent epirubicin toxicities and mediate regression of triple negative breast cancers., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Enhancing chemotherapeutic efficiency through improved drug delivery would facilitate treatment of chemoresistant cancers, such as recurrent mammary tumors and liver cancer. One way to improve drug delivery is through the use of nanodiamond (ND) therapies, which are both scalable and biocompatible. Here, we examined the efficacy of an ND-conjugated chemotherapeutic in mouse models of liver and mammary cancer. A complex (NDX) of ND and doxorubicin (Dox) overcame drug efflux and significantly increased apoptosis and tumor growth inhibition beyond conventional Dox treatment in both murine liver tumor and mammary carcinoma models. Unmodified Dox treatment represents the clinical standard for most cancer treatment regimens, and NDX had significantly decreased toxicity in vivo compared to standard Dox treatment. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for overcoming chemoresistance and enhancing chemotherapy efficacy and safety.

Nanodiamond materials can serve as highly versatile platforms for the controlled functionalization and delivery of a wide spectrum of therapeutic elements. In this work, doxorubicin hydrochloride (DOX), an apoptosis-inducing drug widely used in chemotherapy, was successfully applied toward the functionalization of nanodiamond materials (NDs, 2-8 nm) and introduced toward murine macrophages as well as human colorectal carcinoma cells with preserved efficacy. The adsorption of DOX onto the NDs and its reversible release were achieved by regulating Cl- ion concentration, and the NDs were found to be able to efficiently ferry the drug inside living cells. Comprehensive bioassays were performed to assess and confirm the innate biocompatibility of the NDs, via real-time quantitative polymerase chain reaction (RT-PCR), and electrophoretic DNA fragmentation as well as MTT analysis confirmed the functional apoptosis-inducing mechanisms driven by the DOX-functionalized NDs. We extended the applicability of the DOX-ND composites toward a translational context, where MTT assays were performed on the HT-29 colon cancer cell line to assess DOX-ND induced cell death and ND-mediated chemotherapeutic sequestering for potential slow/sustained released capabilities. These and other medically relevant capabilities enabled by the NDs forge its strong potential as a therapeutically significant nanomaterial.

FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.

Fazarabine (Ara-AC), a structural analog derived from the antitumor nucleoside cytosine arabanoside (Ara-C) and 5-azacytidine (5-AC), was studied in a phase I clinical trial. Doses ranging from 0.2 to 2.0 mg m-2 h-1 were given intravenously over 72 h every 28 days. The maximum tolerated dose (MDT) was 2.00 mg m-2 h-1. The dose-limiting toxicity was myelosuppression, with granulocytopenia being quantitatively more important than thrombocytopenia or anemia. Nonhematologic toxicity was minimal. Associated with the solvent dimethylsulfoxide (DMSO) was a bitter taste and a garlic-like odor.

FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3-4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.

The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

A radioimmunoassay for IMPY has been developed using [3H]acetyl-IMPY and antibody induced by immunizing rabbits with succinyl-IMPY bovine serum albumin conjugates. The method was reproducible and sensitive at a dose of 0.2 microgram/ml. The cross-reactivities of IMPY and IMPY derivatives with the antibody were compared. Using this radioimmunoassay, clinical pharmacology was performed in cancer patients during phase I trials. Following 30-60-minute iv infusions of IMPY (450-1500 mg/m2/day for 5 days), the drug disappeared rapidly from plasma with an initial half-life of less than 10 minutes and second half-life of 4 hours. The half-lives are not affected by minimally abnormal hepatic function and are not dose-related. The apparent volume of distribution was approximately 125 ml/kg. The results obtained on Day 5 were essentially the same as those obtained on Day 1. IMPY was also detected in glioblastoma, brain, and temporalis muscle when the drug (500 mg/m2) was infused iv 4-5 hours before surgery. The tissue drug levels were comparable to or higher than those of plasma. The drug was also measurable in kidney and liver tissues obtained 4 hours after death in a patient who died 21 hours after iv infusion of IMPY at a dose of 1500 mg/m2/day for 3 days.

Tetraplatin (tetrachloro[d,l-trans]1,2-diaminocyclohexane platinum IV (TTP)) is a new platinum analogue active against L1210 murine leukemia that is resistant to cisplatin (diamminedichloroplatinum II (DDP)). Since nephrotoxicity is a significant problem with DDP therapy, we compared the effects of equitherapeutic doses of TTP and DDP on renal structure and function in rats. We also studied the effects of the 2 platinum compounds on the distribution and excretion of gentamicin (GENT), an antibiotic that is excreted solely by the kidneys. Rats treated intravenously with 2.85 mg/kg of DDP on days 1, 5 and 9 had significantly different plasma urea nitrogen (BUN) levels and creatinine clearance rates on day 16 than those given the same doses of TTP. The renal function of TTP-treated rats did not differ from that of controls or rats given only GENT. Twenty-four hours after a single GENT dose (given on day 15), DDP-treated rats had higher GENT concentrations in the plasma, liver and spleen than rats given GENT alone. TTP-treated rats had higher GENT levels only in the spleen. DDP-treated rats retained a higher percentage of the injected platinum in the renal cortex than those treated with TTP. Light microscopic examination of renal tissue showed necrotic cells and dilated tubules in the proximal tubules of DDP-treated rats while the kidneys of TTP-treated rats were largely indistinguishable from those of controls. Thus, our results indicate that the distribution of platinum in the kidneys differs between rats treated with TTP and those treated with DDP. This may partly explain the considerably lower nephrotoxicity of TTP.

N-methyliminodiacetato(1,2-diaminocyclohexane)-platinum(II) (MIDP) is a new third-generation water-soluble antitumor platinum complex. This study compares the effects of MIDP (3 injections of 25 mg/kg each on days 1, 5 and 9) on renal structure and function and the urinary excretion of gentamicin (GENT) with those of a single 6 mg/kg dose of cisplatin (DDP) in F-344 (Fischer) rats. GENT was given as a single dose of 30 mg/kg 7 days after DDP injection or the last MIDP injection. Rats given DDP and GENT had significantly different plasma urea nitrogen (BUN) levels (315 +/- 79 mg/dl) and creatinine clearance (0.40 +/- 0.24 ml/[min.kg]) than did the control group that was given only GENT (15 +/- 1 mg/dl and 5.5 +/- 0.6 ml/[min.kg]). MIDP did not affect renal function (BUN, 16 +/- 3 mg/dl; creatinine clearance, 6.1 +/- 1.0 ml/[min.kg]). Light microscopic examination of renal tissue from MIDP-treated rats did not reveal any evidence of cell degeneration or necrosis. Rats given GENT alone excreted 72 +/- 4% of the dose in 24 h and had plasma gentamicin levels of 19 +/- 2 ng/ml 24 h after injection. The group pretreated with DDP had lower urinary GENT excretion (31 +/- 10%) and higher plasma GENT levels (7491 +/- 3750 ng/ml). MIDP pretreatment had no effect on GENT excretion (72 +/- 8%) or plasma GENT levels (16 +/- 2 ng/ml). Thus, MIDP did not cause any measureable decrease in renal function or GENT excretion in our study. Since nephrotoxicity is a significant problem with DDP administration, further studies with MIDP are warranted.

Immune-mediated hemolytic disease is a phenomenon rarely encountered with cancer chemotherapeutic agents. Elliptinium, a tetracyclic ammonium compound used in breast and kidney cancer, can induce antibodies that may result in clinical hemolysis. This study reports the characterization of the elliptinium haptenic determinant by use of two different methodologies: a hemagglutination test and a radioimmunoassay. Binding of 12 analogues or derivatives of elliptinium was also studied. Good correlation between the two methods was obtained, indicating that the determinant is most likely located on the quaternary ammonium-containing ring. Furthermore, the hydrophilicity of the drug appears to be an important factor in the antibody reaction. The mechanism of the binding of elliptinium to its antibodies is discussed.

The tissue distribution of BAF was compared by intravenous and subcutaneous injections in rats bearing Walker 256 carcinoma. Following a single dose (6 mg/kg containing 30 microCi 4,6-di-14C-BAF), the drug concentrations were determined by radiochemical and dihydrofolate reductase assays. The two methods gave comparable results. No metabolites were found by paper chromatographic separations.

The disposition and metabolism of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide HCl, or LY 195448 (LY), were studied in rodents 1 hr following a single iv injection of 14C-LY at 30 mg/m2 (10 mg/kg mice and 5 mg/kg rats), In all tissues and carcases, recovery of 14C was nearly complete. The majority of radioactivity was recovered from intestine (40%) whereas liver and urine accounted for 10% each, kidney for 3-5%, and plasma for 1-3% of total administered radioactivity. Analyzing by HPLC and TLC, para-hydroxy-LY (para-OH-LY) in addition to unchanged drug, was found in all tissues. Meta-OH-LY was detected only in urine, intestine and kidney. These metabolites were found to be conjugated with either glucuronide or sulfate moieties. Peaks coeluting with authentic para-OH-meta-methoxy-LY and di-OH-LY were also observed.

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.

Medium-sized peptides isolated from normal humans urine were tested for their effect on DNA, RNA, and protein synthesis, and mitosis, in tissue culture of human myeloblastic leukemia, osteosarcoma, and HeLa cells. Two types of antineoplastic peptides were found. One type consists of strongly acidic peptides (probably sulfated glycopeptides) which act specifically on different kinds of neoplasma. The other type comprises slightly acidic and neutral peptides, and has broad specificity. The active peptides produce up to 97% inhibition of DNA synthesis and mitosis in the neoplastic cells in tissue culture. The peptide fraction which has broad specificity was tested in different concentrations and gave good dose-response relationship.

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction. [ABSTRACT FROM AUTHOR]