High Antineoplastic Activity Research Articles

Solvent-dependent crystallization and anti-cancer activities based on Ni(II) and Co(II) complexes of 1-picolinoyl-4-phenyl-3-thiosemicarbazide: Synthesis, crystal structure, and photoluminescence study

In search of alternative of platinum-based drugs for the treatment of cancer, lead to the development of other potential metallodrug of transition metal complexes. The efficacious and novel experimental content of this paper reports the synthesis of [Ni(Hppts)2].CHCl3 (1a), [Ni(Hppts)2].(CH3)2SO (1b) and [Co(Hppts)2] (2) complexes of 1-picolinoyl-4-phenyl-3-thiosemicarbazide (H2ppts). The synthesized complexes have been characterized by UV-vis., Infrared, and NMR spectrometry. Furthermore, complexes 1a and 1b were characterized by single-crystal X-ray diffraction data. Emission spectra show that, complex 1a exhibits higher fluorescence intensity as compared to that of ligand H2ppts and complex 2. The order of fluorescence intensity was found as complex 1a > complex 2 > H2ppts. Moreover, Complexes 1a and 1b are stabilized via various types of intermolecular interactions. The cytotoxicity of complexes 1a, 2, and ligand was evaluated against Dalton's Lymphoma cells using standard MTT Assay. The anticancer activity results showed that complex 1a significantly reduced cell viability in a dose-dependent manner, whereas H2ppts and complex 2 did not show significant reduction in cell viability of DL cells when compared with the control. The complex 1a IC50 value was determined to be around 40 µg/mL. The anti-tumor activity concludes that the complex 1a has high anti-neoplastic activity on DL cells at low doses.

Anti-PD-1/PD-L1 immunotherapy in conversion treatment of locally advanced hepatocellular carcinoma.

Curative surgery and locoregional therapy are radical therapies for patients with HCC. But more than 80% of HCC patients cannot be fitful for radical therapies because of local progression or distant metastasis at initial diagnosis. Among patients with unresectable locally advanced hepatocellular carcinoma (HCC), some patients can be converted to be technically resectable by conversion treatment and salvage surgery. For unresectable locally advanced hepatocellular, conversion treatment prior to salvage surgery with transcatheter arterial chemoembolization (TACE) and other locoregional therapies improve outcomes. PD-1/PD-L1 inhibitors as immune checkpoint inhibitor (ICI) therapy which show high antineoplastic activity in HCC patients by preclinical and clinical researches can also be a good choice for conversion therapy. PD-1/PD-L1 inhibitor combined with locoregional therapy plus antiangiogenic agents or not is most potential conversion therapy comparing to PD-1 inhibitor monotherapy and PD-1/PD-L1 inhibitor combined with antiangiogenic agents or CTLA-4 inhibitor. As more clinical evidence reported, PD-1/PD-L1 immunotherapy would be widely used in conversion treatment of locally advanced hepatocellular carcinoma.

Synthesis and bioactivities of new N-terminal dipeptide mimetics with aromatic amide moiety: Broad-spectrum antibacterial activity and high antineoplastic activity

The increasingly growing epidemics of multidrug-resistant bacteria are becoming severe public health threat. There is in an urgent need to develop new antibacterial agents with broad-spectrum antibacterial activity and high selectivity. Here, a series of N-terminal dipeptide mimetics with an aromatic amide moiety were synthesized from amino acids. The effects of amino acid type and aromatic moiety on the biological activities of the mimetics were evaluated. The dipeptide mimetics not only showed significant broad-spectrum antibacterial activity against Gram-negative (Escherichia coli and Klebsiella pneumoniae), Gram-positive (Staphylococcus aureus) and drug-resistant bacterium MRSA (methicillin-resistant S. aureus) but also demonstrated high selectivity for S. aureus versus mammalian erythrocytes. The coupling product of L-valine with p-alkynylaniline (dipeptide mimetic 7) exhibited the best antibacterial activities with minimum inhibitory concentration (MIC) ranging from 2.5 to 5 μg/mL. Moreover, the bactericidal kinetics and multi-passage resistance tests indicated that the mimetic 7 both rapidly killed bacteria and had a low probability of emergence of antimalarial resistance. Meanwhile, the mimetic 7 possessed the ability to both inhibit bacterial biofilm formation and eradicate mature biofilm. The depolarization and destruction of the bacterial cell membrane is the main sterilization mechanism, which hinders the propensity to develop bacterial resistance. Furthermore, the mimetic 7 also showed good antineoplastic activity against gastric cancer cell (SGC 7901, IC50 = 70.8 μg/mL), while it had very low toxicity to mammalian cell (L929). The mimetics bear considerable potential to be used as antibacterial and anticancer agents to combat antibiotic resistance.

Preparation of gardenia red pigment and its antineoplastic activity in multiple tumor cells

Gardenia red pigment, also referred to genipin red, is a natural food colorant used in the food industry. It is produced by the reaction of amino acids with genipin, the aglycon of geniposide acid (GPA) and geniposide, which is abundant in the by-products of gardenia yellow production. However, due to the high content of impurities, gardenia red pigment production shows low color value and purity, which limits its application. In this study, the preparation and purification of gardenia red pigments using by-products of gardenia yellow production as raw materials were investigated. Purified geniposidic acid and genipin were obtained and reacted with His to give gardenia red. After optimization, gardenia red with high color value (117) and purity (91.1%) was obtained. Furthermore, the in vitro biological functional assays suggested that gardenia red pigments showed high antineoplastic activity with H1299, A375 and MCF-7 cancer cells. This study has developed an optimized preparation process and shown potential functions of gardenia red.

Cyclometalated Ir(III)-8-oxychinolin complexes acting as red-colored probes for specific mitochondrial imaging and anticancer drugs

A new class of luminescent IrIII antitumor agents, namely, [Ir(CP1)(PY1)2] (Ir-1), [Ir(CP1)(PY2)2] (Ir-2), [Ir(CP1)(PY4)2] (Ir-3), [Ir(CP2)(PY1)2] (Ir-4), [Ir(CP2)(PY4)2] (Ir-5), [Ir(CP3)(PY1)2]⋅CH3OH (Ir-6), [Ir(CP4)(PY4)2]⋅CH3OH (Ir-7), [Ir(CP5)(PY2)2] (Ir-8), [Ir(CP5)(PY4)2]⋅CH3OH (Ir-9), [Ir(CP6)(PY1)2] (Ir-10), [Ir(CP6)(PY2)2]⋅CH3OH (Ir-11), [Ir(CP6)(PY3)2] (Ir-12), [Ir(CP6)(PY41)2] (Ir-13), and [Ir(CP7)(PY1)2] (Ir-14), supported by 8-oxychinolin derivatives and 1-phenylpyrazole ligands was prepared. Compared with SK-OV-3/DDP and HL-7702 cells, the Ir-1−Ir-14 compounds exhibited half maximal inhibitory concentration (IC50) values within the high nanomolar range (50 nM−10.99 μM) in HeLa cells. In addition, Ir-1 and Ir-3 accumulated and stained the mitochondrial inner membrane of HeLa cells with high selectivity and exhibited a high antineoplastic activity in the entire cervical HeLa cells, with IC50 values of 1.22 ± 0.36 μM and 0.05 ± 0.04 μM, respectively. This phenomenon induced mitochondrial dysfunction, suggesting that these cyclometalated IrIII complexes can be potentially used in biomedical imaging and Ir(III)-based anticancer drugs. Furthermore, the high cytotoxicity activity of Ir-3 is correlated with the 1-phenylpyrazole (H-PY4) secondary ligands in the luminescent IrIII antitumor complex.

Investigation of Mechanism Activity of Antitumor and Radiosensitizing Activity of Preparations К-26 and K-26w

Introduction. Tropolone alkaloid – colchicine, there is very interesting object for synthesis of its derivatives, with such properties as, alkylation, a low toxicity, high antineoplastic activity and especially overcoming of multidrug resistance (MDR). We had been developed the antineoplastic preparation К-26 derivative of colchicine. К-26 has shown high cytotoxic activity on 60 lines of tumoral cells of the human in vitro, at National Institute of the Cancer of the USA (NCI). Further on the basis of К-26 its water-soluble form named term К-26w has been received. The work purpose. Studying of the mechanism of action of preparations К-26 and К-26w on: alkylating ability, mitotic activity, topoisomerase II, MDR2, р53 and colony-forming cells spleen (CFCs). Materials and methods. All researches have been carrying out by a standard technique. Studying mitotic activity of preparations was carrying out on duodenum and tumor СаРа after preparation influence. On models of a tumor of the Sarcoma 180 action of preparations has been investigated: the alkylating - on synthesis DNA/RNA, nucleosoma DNA degradation, activity topoisomerase II; on an expression MDR2 and р53 genes. Studying CFCs carry out by a standard technique on outbred mice. Results. К-26, К-26w and etoposide inhibited in cells of the Sarcoma 180: synthesis DNA/RNA on 84/65%, 95/85% and 55/35%, accordingly, in relation to the control; activity topoisomerase II on 80%, 90% and 60% accordingly. By method RT-PCR it is shown, К-26, К-26w and etoposide: inhibited an expression of MDR2 gene on 83%, 91% and 62%; increase expression р53 gene to 74%, 88% and 55%, accordingly, under the relation of the control of referential gene GARDH (100%). High ability К-26 and К-26w in an induction apoptosis tumoral cells and CFCs to 12 units is shown. Conclusion. Revealed ability К-26 and К-26w to suppress synthesis DNA/RNA activity topoisomerases, to stimulate р53, and also to suppress an expression of a multidrug resistance MDR2 gene, it explains their high antineoplastic activity which is connected with mitotic activity leading to cell fission synchronization, and radiosensitization activity. Special interest represents found at К-26w and К-26 suppression MDR2 as they are aimed for treatment of such resistant tumor as a kidney cancer. Stimulation CFCs which provides formation of haemopoetic and immune cells can protect an organism from their intensive cytotoxic action.

Hydroperoxides derived from marine sources: origin and biological activities.

Hydroperoxides are a small and interesting group of biologically active natural marine compounds. All these metabolites contain a group (R-O-O-H). In this mini-review, studies of more than 80 hydroperoxides isolated from bacteria, fungi, algae, and marine invertebrates are described. Hydroperoxides from the red, brown, and green algae exhibit high antineoplastic, anti-inflammatory, and antiprotozoal activity with a confidence of 73 to 94%. Hydroperoxides produced by soft corals showed antineoplastic and antiprotozoal activity with confidence from 81 to 92%. Metabolites derived from sea sponges, mollusks, and other invertebrates showed antineoplastic and antiprotozoal (Plasmodium) activity with confidence from 80 to 90%.

Novel dihydropyrimidine derivatives as potential HDAC inhibitors: in silico study.

Dihydropyrimidine derivatives possess many biological activities due to presence of pyrimidine ring structure in various nucleic acids, vitamins, coenzymes, uric acid and their derivatives. They have possessed broad spectrum actions like antibacterial, antifungal, antiviral, anticancer and antihypertensive etc. Before synthesis of compounds, it is good to predict biological activity using in silico methods. Here, we have selected some of N (3a-f) and O (4a-f) mannich bases of dihydro pyrimidine derivatives emphasized on histone deacetylase 4 (HDAC-4) inhibitions activity. We have used the different software tools like Lipinski's rule of five; pass online; osiris property explorer and docking studies to predict anti cancer activity. All the selected compounds exhibited potential drug like molecule with anti cancer activity. Among all compound the substitution with methoxy group (3c) exhibited more drugs like property and substation with hydrogens (4a) showed high anti neoplastic activity; whereas substitution with dichloro groups (4e) showed more drug docking scores. These were compared with standard drugs tamoxifen and 5-flourouracil. The approach of predicting anticancer activity using in silico method may be more useful to select and synthesis novel compounds in research as well as in industry.

BSA-conjugated CdS/Ag2S quantum dots: synthesis and preliminary antineoplastic assessment

Tumours are one of the most difficult diseases to cure, and traditional chemotherapy drugs are always intimidating for use in tumour treatments because of their highly toxic side effects. This drives the research and development of innovative drugs. As a product, nanomaterials, particularly nano-drugs, are exhibiting great potential for use in tumour treatments. Based on the understanding of the Trojan horse-antineoplastic mechanism of nano-drugs, we tried to introduce the drug-combination opinion into nano-drugs and successfully developed a facile and eco-friendly synthesis route to fabricate bovine serum albumin-conjugated CdS/Ag2S quantum dots. It is notable that the double metallic sulphides showed a synergistic inhibition between Cd2+ and Ag+ on rat pheochromocytoma (PC 12) cells. Summarily, the present study substantiated the potential of synergistic anti-cancer opinion at the design of innovative nano-drugs with higher antineoplastic activity.

Mycelial antineoplastic activity of Agaricus blazei.

Basidiocarp of Agaricus blazei (=Agaricus brasiliensis; =Agaricus subrufescens) is used as teas or capsules due to its antineoplastic effect but there are few reports of using mycelium for this purpose. The objective of this study was to evaluate the antineoplastic activity on sarcoma 180 cells implanted in mice of two forms of preparation of the mycelium from two A. blazei strains grown in culture medium with different concentrations of isolated soy protein. Mycelia were grown in Pontecorvo medium with different concentrations of isolated soybean protein (ISP). Mycelial hot water extract, moistened mycelial powder, hot water extract of green tea, Ifosfamida(®) (ifosfamide drug), and saline solution were administered daily by gavage in mice with sarcoma 180 cells to evaluate antineoplastic activity. It was concluded that antineoplastic activity was the same for both strains, except when used as moistened mycelial powder, which rules out the use of mycelial powder in capsules. Mycelial hot water extract had high antineoplastic activity with lower metabolic demand on the spleen and maintenance of normal blood parameters. Mycelial growth in different ISP concentrations had the same antineoplastic activity. Also the vegetative mycelium was as effective as the basidiocarp for sarcoma 180 tumor inhibition. Green tea was as effective as mycelial hot water extract.

An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

(−)-Agelastatin A (AA), isolated from the coral sea axinellid sponge Agelas dendromorpha, has shown a high antineoplastic activity. We have synthesized eighteen AA analogues and analyzed their cytotoxicities towards three cancer cell lines. By the structure–activity relationship (SAR) study, we identified three novel analogues with higher or comparable cytotoxic activities to AA. They were subjected to chemoinformatic analysis, which revealed physicochemical properties favoring excellent central nervous system (CNS) penetration. CNS pharmacokinetic analysis in murine models validated the chemoinformatic prediction and revealed that these analogues indeed had better CNS penetration than AA. These novel potent AA analogues deserve further evaluation for therapeutic use against cancers, particularly primary and secondary brain tumors.

Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins

This study investigated the antineoplastic effect of the membrane active alkylphosphocholine erufosine in breast carcinoma models in vitro and in vivo and determined its influence on the PI3K/Akt and Ras/Raf/MAPK signaling pathways. The antiproliferative effect of erufosine in vitro was determined by the MTT dye reduction assay, and the antineoplastic efficacy on tumor growth was investigated by relating the mean total tumor volumes of treated and control rats. Immunoblot analysis was used for detecting changes in the expression level of the signal molecules p-PI3K (p-p85), p-Akt at Thr 308 and p-cRaf. Based on their IC(50) (40 μM, respectively), the breast carcinoma cell lines MCF-7 and MDA-MB 231, which are estrogen receptor positive and negative, respectively, were equally sensitive to erufosine. In addition, erufosine caused dose-dependent decreases in the phosphorylation of PI3K (p85), Akt (PKB) at Thr 308 and cRaf in both cell lines. Moreover, administration of erufosine to rats bearing autochthonous methylnitrosourea-induced rat mammary carcinomas caused a significant dose-related tumor remission by more than 85 % (p < 0.05), which was well tolerated, as evidenced by a body weight loss of maximally 7 % and reduced tumor-related mortality (2 of 35 instead of 6 of 18 controls, p < 0.002). The results clearly indicate that erufosine possesses high antineoplastic activity not only in human breast cancer cell lines in vitro but also in rat mammary carcinoma in vivo. In addition, it can be derived that the mechanism of action of erufosine involves influence on both, PI3K/Akt and Ras/Raf/MAPK signaling pathways.

Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma

DNA methylation is an epigenetic mechanism establishing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) is able to reactivate genes silenced by DNA methylation and has been shown to be a very potent epigenetic drug in several hematological malignancies. In this report, we demonstrate that 5-aza-CdR exhibits high antineoplastic activity against anaplastic large cell lymphoma (ALCL), a rare CD30 positive non-Hodgkin lymphoma of T-cell origin. Low dose treatment of ALCL cell lines and xenografted tumors causes apoptosis and cell cycle arrest in vitro and in vivo. This is also reflected in genome-wide expression analyses, where genes related to apoptosis and cell death are amongst the most affected targets of 5-aza-CdR. Furthermore, we observed demethylation and re-expression of p16INK4A after drug administration and senescence associated β-galactosidase activity. Thus, our data provide evidence that 5-aza-CdR is highly efficient against ALCL and warrants further clinical evaluation for future therapeutic use.

The histone deacetylase inhibitors suberoylanilide hydroxamic (Vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells

Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA, Vorinostat), valproic acid (VPA), and FK228 are members of a relatively novel class of small molecular weight chemicals that have high antineoplastic activity. They cause growth inhibition and apoptosis specifically in tumor cells, and they act also as chemo- and radio-sensitizers. In the present study, the potential of SAHA and VPA to induce resistance was studied. To that aim HDAC inhibitor-resistant sublines were generated by stepwise exposure of colon tumor cells to increasing concentrations of these compounds. Clonogenic data demonstrated that the SAHA- and VPA-induced sublines were 2-fold resistant to these compounds. This resistance was non-reversible, as it was maintained even when the sublines were cultured in the absence of SAHA or VPA. The SAHA- and VPA-induced resistant sublines were also stably cross-resistant to VPA and SAHA, respectively, but retained sensitivity against non-HDAC inhibitor-type anticancer agents. The SAHA-induced resistance correlated with loss of the G2/M checkpoint but it was not accompanied by reduced induction of the endogenous cell cycle inhibitors p21 and p27. Furthermore, SAHA-induced resistance was not due to reduced apoptosis, and it was neither dependent on MDR expression nor was it due to increased expression of HDAC1 and HDAC3. Taken together, these data demonstrate the potential of SAHA and VPA to induce resistance. This resistance was not dependent on MDR expression, did not involve MMR, and seemed to underlie a mechanism that differs from that underlying the previously observed FK228-induced resistance. The finding that SAHA and VPA induce only modest resistance despite continuous treatment and that the resistance is MDR-independent suggests a preference for these two drugs over FK228 for use in combination treatment with classic anticancer agents.

High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA topoisomerase II‐targeting drugs

Twenty previously synthesized fused heterocyclic DNA-topoisomerase II (Topo II)-inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities. Moreover, different multidrug-resistant variants of these cancer cell lines with decreased Topo II expression were investigated. In parental, drug-sensitive cells merely the compounds BD3 and G35 showed efficacies, in terms of microM, which were similar to that of the classical Topo II inhibitor etoposide. On the other hand, most of the tested heterocyclic compounds were found more effective in drug-resistant cells than in the parental, drug-sensitive ones, and some of the compounds showed high antineoplastic efficacy in several drug-resistant cell models. Compounds BD13, BD14 and BD16 exhibited high antineoplastic activities against the drug-resistant sublines EPG85-257RNOV and EPG85-257RDB derived from gastric carcinoma, EPP85-181RNOV and EPP85-181RDB derived from pancreatic carcinoma, MCF-7/Adr derived from breast cancer, D79/86RNOV derived from fibrosarcoma, and MeWoETO1 derived from melanoma. Furthermore, compound D23 was found highly efficient in the multidrug-resistant variants HT-29RNOV and HT-29RDB derived from colon carcinoma, and compound D24 exhibited the highest antineoplastic activity among the tested compounds in the drug-resistant subline MDA-MB-231ROV derived from breast cancer. In conclusion, compounds BD 13, BD 14, BD 16, D 23 and D 24 may be useful for the treatment of different multidrug-resistant cancer cells with cross resistance against "classical" Topo II-targeting drugs.

Toxic effects of copper-based antineoplastic drugs (Casiopeinas ®) on mitochondrial functions

To elucidate some of the subcellular and biochemical mechanisms of toxicity of metal-based antineoplastic drugs, mitochondria and cells were exposed to Casiopeinas ®, a new class of copper-based compounds with high antineoplastic activity. The rates of respiration and swelling, the H + gradient, and the activities of succinate (SDH) and 2-oxoglutarate dehydrogenases (2-OGDH) and ATPase were measured in mitochondria isolated from rat liver, kidney, heart, and hepatoma AS-30D. Also, oligomycin-sensitive respiration and ATP content in hepatoma AS-30D cells were determined. Casiopeinas ® (CS) II-gly and III-i inhibited the rates of state 3 and uncoupled respiration in mitochondria. CS II was 10 times more potent than CS III. The sensitivity to CS II was 4–5-fold higher in mitochondria incubated with 2-OG than with succinate. Thus, at low concentrations (≤10 nmol (mg protein) −1; 10 μM), CS II disturbed mitochondrial functions only when 2-OG was present, due to a specific inhibition of 2-OGDH. At high concentrations (≥15 nmol (mg protein) −1), CS II-induced stimulation of basal respiration, followed by a strong inhibition, which correlated with K +-dependent swelling and cytochrome c release, respectively; K +-channel openers induce a similar mitochondrial response. Mitochondria from liver, kidney and hepatoma showed a similar sensitivity towards CS II, whereas heart mitochondria were more resistant. Oxidative phosphorylation and ATP content were also decreased in tumor cells by CS II. The data suggested that CS affected several different mitochondrial sites, bringing about inhibition of respiration and ATP synthesis, which could compromise energy-dependent processes such as cellular duplication.

Synthesis and biological activity of a fluoroketonucleoside: 7-(3-deoxy-3-fluoro-β- d- glycero-hex-2-enopyranosyl-4-ulose)theophylline

The title compound 5 was synthesized by direct oxidation of the fluoro precursor and not from an epoxyketo intermediate according to the Paulsen procedure, which has been used until now to obtain bromo- and chloro-ketonucleosides. Antineoplastic activity and immunosuppressive effect of 5 were studied on murin splenic lymphocytes (steady state or stimulated by PHA), and on RAJI and DAUDI cells, and compared with the activity of 3-(3-deoxy-β- d- glycero-hex-2-enopyranosyl-4-ulose)thymine. IC 50 values showed that the fluoroderivative 5 has a higher antineoplastic activity and a lower immunosuppressive effect.

Synthesis of the spin-labeled derivative of an ether-linked phospholipid possessing high antineoplastic activity

We report here the complete synthesis of the spin-labeled derivative of an antitumor ether phospholipid, 1- O-octadecyl-2- O-(4′-doxylpentyl- rac-glycerol-3-phosphocholine. This also represents the first time that the synthesis of a nitroxide spin-labeled diether phospholipid is described. In vitro experiments showed that at micromolar concentrations, this new analog is readily incorporated into the plasma membranes of human HL60 and mouse E8/AK.D1 leukemic cells, and subsequently kills the cells. The availability of this new probe should permit the electron spin resonance spectroscopic approach to investigate ways by which antitumor ether phospholipids selectively destroy the tumor cells.

Cholesterol Sulfate-Containing Liposomes Entrapping Adriamycin. Pharmacokinetics and Antineoplastic Effect.

Pharmacokinetics and antineoplastic effect of adriamycin (ADM) entrapped in multilamellar vesicles of liposomes composed of egg phosphatidylcholine (PC), cholesterol (Chol), and cholesterol sulfate (CholSO4) in a molar ratio of 6:3:1 were studied. Upon its intravenous injection, the blood level of ADM remained higher for 24h than that of ADM entrapped in liposomes composed of PC, Chol, and sulfatide (CSE) in a molar ratio of 5:4:1 and than that of free ADM. Entrapment of ADM in liposomes containing either CholSO4 or CSE reduced the concentration of ADM in the heart and kidney compared with free ADM. In the liver, however, the level of ADM, when the drug entrapped in CholSO4-containing liposomes was injected, was similar to that of ADM injected in free form, while the drug markedly accumulated in this organ, when ADM was entrapped in CSE-containing liposomes. By using P388 leukemia of mice, we demonstrated that ADM entrapped in CholSO4-containing liposomes has higher antineoplastic activity than free ADM.

The pharmacokinetic model and distribution pattern of new sexual-steroid-hormone-linked anticancer agents

Sexual-steroid-hormone-linked anticancer agents are a new group of cytotoxic drugs designed for a site-directed chemotherapy of tumors containing sexual steroid hormone receptors. The hormone (e.g. estradiol or testosterone) should act as a carrier that leads to a preferential receptor-mediated drug accumulation in hormone-receptor-positive tumors (such as mammary carcinomas and prostatic cancer). In several preclinical therapeutic studies of sexual-hormone-receptor-positive breast cancer, for instance, conjugates of 2-chloroethyl-carbamoyl-L-alanine linked to estradiol or dihydrotestosterone showed, in comparison to the unlinked single agent, a significantly higher antineoplastic activity and a clearly lower systemic toxicity. But there is still only limited knowledge about the pharmacokinetic properties and the mode of action of these new drugs. For this reason in the present article a more comprehensive pharmacokinetic model and the pattern of distribution of new sexual-steroid-hormone-linked anticancer agents have been described.