Hans R Hendriks

Hans R Hendriks
Hendriks Pharmaceutical Consulting · -

PH.D.
Consulting and due diligence of anticancer drug development, Scientific and (regulatory) medical writing.

About

86
Publications
9,502
Reads
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1,689
Citations
Additional affiliations
January 2000 - March 2020
Hendriks Pharmaceutical Consulting
Hendriks Pharmaceutical Consulting
Position
  • Managing Director
May 1989 - January 2000
Amsterdam University Medical Center
Position
  • Head of Department
August 1974 - May 1989
Vrije Universiteit Amsterdam
Position
  • Professor (Assistant)

Publications

Publications (86)
Article
Full-text available
MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound’s therapeutic potential in vitro u...
Poster
4HF Biotec recently developed an in-silico platform dedicated to cancer data investigations. It connects cancer-related molecular and drug sensitivity information enabling target and biomarker discovery. We used the platform to perform an integrative pharmacogenomic study for the CDK4/6 inhibitor Palbociclib. CDK4/6 inhibitors are molecules blockin...
Conference Paper
Full-text available
MEK inhibitors emerged as a promising class of anti-cancer agents to inhibit KRAS/RAF driven tumors like melanoma and colorectal cancer. GDC-0623 is a potent ATP-noncompetitive allosteric MEK1 inhibitor. The compound forms a strong hydrogen bond with Ser212 of MEK1, blocking MEK feedback phosphorylation of wild-type RAF. Preclinical studies showed...
Poster
The BET family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) has emerged as a promising new cancer target for small-molecule drug discovery. GSK 1324726A (I-BET726) is a highly selective inhibitor of BET family proteins that binds BRD2, BRD3 and BRD4 with IC50 of 41 nM, 31 nM, and 22 nM, respectively. In the present study, we aimed to identi...
Article
Full-text available
Progress in and better understanding of cancer biology causes a shift in cancer drug development: away from the evaluation of drugs in large tumour histology defined patient populations towards targeted agents in increasingly heterogeneous molecularly defined subpopulations. This requires novel approaches in clinical trial design by academia and in...
Article
Full-text available
p>Drug development consists of many sequential and parallel steps; failure in one of the steps can lead to discontinuation of the process. The process is time-consuming and very expensive, especially the clinical phase. In order to enhance cancer drug development in the 1980s, the National Cancer Institute (NCI) adopted a new screening system using...
Conference Paper
The p38 MAPK pathway, also called stress activated protein kinase pathway, is involved in basic cellular processes of inflammation and acts on cell growth, proliferation, differentiation, migration, and apoptosis. p38 MAP kinase activation occurs by environmental stress and proinflammatory cytokines signaling and is frequently deregulated in cancer...
Article
Full-text available
Introduction: Apaziquone (also known as EO9 and Qapzola) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered int...
Article
Background: The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in v...
Article
Full-text available
During the last decade, novel immunotherapeutic strategies, in particular antibodies directed against immune checkpoint inhibitors, have revolutionized the treatment of different malignancies leading to an improved survival of patients. Identification of immune-related biomarkers for diagnosis, prognosis, monitoring of immune responses and selectio...
Article
Full-text available
Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment approaches; still, breast cancer-related mortality remains relatively high. Efforts in the field of basic research revealed new druggable targets which now await validation within the context of clinical trials. Therefore, questions concer...
Article
EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered intravenously. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue are the major causative fa...
Article
Full-text available
Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-drug was synthesized (CP-4126),...
Patent
The present invention relates to a method of treating cancer in a subject in need thereof, by administering to the subject a combination of sodium meta arsenite and/or arsenic trioxide and a cytotoxic cancer agent, such as cisplatin, adriamycin, and taxane, such as larotaxel, orataxel, tesetaxel, docetaxel or paclitaxel. The arsenic compound(s) and...
Article
Full-text available
KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase and telomeres. We compared telomere length to KML001 cytotoxic activity in a panel of human solid tumor cell line...
Article
The anti-tumor activity of the putative differentiation-inducing agent dimethylformamide (DMF) was assessed in 7 head-and-neck xenograft (HNX) lines transplanted into nude mice. The drug was administered intra-peritoneally at the maximum tolerated dose. A significant growth-inhibitory effect was observed in 3 out of 7 tumor lines tested. When compa...
Article
Resistance to, the hydrophilic drug ara-C, might be meditated by decreased membrane transport. Lipophilic prodrugs were synthesized to facilitate uptake. These compounds were equally active as ara-C, while the compounds with the shortest fatty-acid group and highest number of double bonds were the more active. These compounds also show a better ret...
Article
Full-text available
A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels o...
Article
Full-text available
In a recent study we demonstrated that recombinant human growth hormone (r-hGH; Saizen) delayed tumor-induced cachexia in human tumor xenografts in vivo. Such a therapeutic effect could have a great impact in the supportive care of advanced cancer patients. Before large clinical studies are initiated possible growth stimulation should be excluded....
Article
Full-text available
Ecteinascidin-743 (ET743) is a novel antitumour agent originating from the Caribbean tunicate Ecteinascidia turbinata. It has potent cytotoxic and antitumour activity and a potential new mechanism of action. The aim of the present study was to further explore the antitumour activity of ET743 in human tumour xenografts from melanoma, non-small-cell...
Article
Full-text available
N-L-leucyl-doxorubicin (Leu-DOX), a prodrug of doxorubicin (DOX), has previously shown antitumour activity against human ovarian, breast and lung carcinomas in nude mice. In the present study, the efficacy of Leu-DOX was compared with free DOX in inhibiting the growth of four DOX-sensitive and -resistant malignant melanoma xenografts. In an attempt...
Article
Full-text available
The antitumour activity of the investigational agent N-L-leucyl-doxorubicin (Leu-DOX) was compared with that of doxorubicin (DOX) in human tumour xenografts growing subcutaneously in athymic nude mice. Leu-DOX was developed as a prodrug of DOX, and may be converted into the clinically active parent compound by hydrolytic enzymes present in or on tu...
Article
Full-text available
The antitumor activity of ecteinascidin (ET)-743, a novel marine natural product, was evaluated against a panel of human ovarian carcinoma xenografts characterized by different malignant behaviors and drug responsiveness in nude mice. These tumor models included three xenografts transplanted s.c. (HOC18, HOC22-S, and MNB-PTX-1) into nude mice, repr...
Article
Full-text available
KW-2149 (7-N-[2-[gamma-L-glutamylamino]ethyldithioethyl]mitomycin C) is a new mitomycin-C analogue in clinical trial. This study demonstrates that KW-2149, unlike mitomycin C, is activated to a cytotoxic species by extracellular metabolism in serum. The metabolising activity differs between batches of serum and species of origin. Human serum had hi...
Article
Full-text available
ET-743 is a novel quinoline alkaloid isolated from a caribbean tunicate. IVT studies identifies activity (A) in A549 lung, HT29colon, and Melmelanoma (MEL) cell lines with IC50s=034,0.60 and 0.66nM rescepctivily. The NCI IVT panel coofirmed A particularly in MEL, NSCLC, breast (B) and Ovarian (O) lines. This A has been validated in the IVT-HTCFU as...
Article
Full-text available
Two series of phosphodiester ether lipid analogs with (N-methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (9-19) was evaluated in vitro against a panel o...
Article
Full-text available
1. The indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2- (1H-indole-4,7-dione)-propenol; E85/053; NSC 382,459) is a synthetic bioreductive alkylating agent that is structurally related to mitomycin C (MMC). 2. EO9 does, however, show a different mechanism of action and a broader antitumour profile than MMC. It is also a more potent cytoto...
Article
Full-text available
Cycloplatam is a novel platinum compound which has shown anti-tumour activity in murine tumour models. In this study, cycloplatam was found to have anti-tumour activity in vitro and in vivo in human tumour models. In 15 cell lines (mainly ovarian), cycloplatam showed similar cytotoxicity as cisplatin, using the sulphorhodamine B assay. Determinatio...
Article
Olomoucine (2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine) has been recently described as a competitive inhibitor (ATP-binding site) of the cell cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5 p35 kinase and the ERK1AP-kinase. The unusual specificity of this compound towards cell cycle regu...
Chapter
Full-text available
The discovery and development of new anticancer agents is a long lasting and complex process requiring large investments in terms of manpower and money. To keep control on such programmes they are usually subdivided into several clearly defined stages. Each stage is devoted to a specific part of the development pathway of the drug with stop/go deci...
Article
Full-text available
The EORTC New Drug Development Office has initiated a multicenter collaborative program to evaluate the use of human tumor xenografts to predict phase II clinical activity. A first study confirmed the efficacy of doxorubicin and inactivity of amsacrine against human tumor xenografts (Boven et al., Cancer Res: 52, 5940, 1992). In the follow-up study...
Article
Full-text available
EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, E09 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, E09 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared...
Conference Paper
Full-text available
Article
Full-text available
The potential of the calcium-entry blocker flunarizine in modulating the cytotoxicity of doxorubicin was investigated in human colon-adenocarcinoma cell lines sensitive to (LoVo) or with experimentally induced resistance (LoVo/DX) to doxorubicin. Exposure to 1 to 2 micrograms/ml flunarizine for intervals of up to 24 hr did not affect cell survival...
Article
Full-text available
N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosen...
Article
Full-text available
Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vin...
Article
With the aim of verifying the concept of osteotic vectorisation, synthesis of three methotrexate (MTX) gem-diphosphonic analogues (compounds A, B and C) was performed. These molecules were tested on BALB/c and NIH III mice previously grafted with subcutaneous implants of OHS, TTX p7 and/or TTX p11 human osteosarcoma cell lines. Antineoplasic activi...
Article
Full-text available
We investigated the antitumoral activity of Dabis Maleate given on different dosage schedules and as continuous infusion in a murine reticular cell sarcoma M5076 (M5) and in a subline made resistant to cyclophosphamide and other nitrogen mustards (M5/CTX). The therapeutic index of Dabis Maleate was clearly better when the drug was given as a contin...
Article
Full-text available
The antitumour activity of the investigational agent vinblastine-isoleucinate (V-LEU) was compared with vintriptol, another investigational agent of the same series of vinblastine-23-oyl amino acid derivatives, and vinblastine, their clinically active parent compound, in a panel of nine human tumour xenografts growing subcutaneously in nude mice. C...
Article
(NDDCC) was created with the purpose to establish a comprehensive anticancer drug development program covering all essential preclinical and clinical stages, a task executed by the New Drug Development Office (NDDO). The NDDCC makes selections of new candidates for development and has established guidelines for the formulation of investigational cy...
Article
Interruption of the afferent lymphatic vessels of rat popliteal lymph nodes led to the disappearance of the monoclonal antibody ED3-reactive subcapsular sinus macrophages within 3 weeks, but had no effect on the ED1+ macrophages in the paracortical area. This disconnection of the afferent lymph flow to the popliteal lymph node also reduced the capa...
Article
Full-text available
The influence of recirculating lymphocytes on the function and morphology of high endothelial venules (HEV) has been studied. Mice were depleted of lymphocytes by lethal (1200 cGy) total body irradiation; subsequently, the HEV in mesenteric and cervical lymph nodes were studied up to 7 days after irradiation for: 1) capacity to bind lymphocytes by...
Article
Recirculating lymphocytes specifically adhere to and migrate through endothelium lining high endothelial venules (HEV), using specific and non-specific receptor-ligand systems. Interferons (IFN) profoundly affect the traffic of lymphocytes. Therefore the effects of interferon-gamma (IFN-gamma) on lymphocytes with respect to their interaction with H...
Article
Full-text available
The anti-tumor activity of the putative differentiation-inducing agent dimethylformamide (DMF) was assessed in 7 head-and-neck xenograft (HNX) lines transplanted into nude mice. The drug was administered intra-peritoneally at the maximum tolerated dose. A significant growth-inhibitory effect was observed in 3 out of 7 tumor lines tested. When compa...
Article
Full-text available
Lymphocyte migration and recirculation between lymphoid and also nonlymphoid tissues is essential for effective immunological surveillance. The entrance of blood-borne lymphocytes into peripheral lymphoid organs, such as lymph nodes and Peyer’s patches, occurs at particular vascular sites, so called post-capillary high endothelial venules (HEV;1,2)...
Article
Recirculating lymphocytes migrate from the blood into lymph nodes through the walls of the high endothelial venules (HEV). HEV are lined by large plump so-called high endothelial cells (HE cells) to which lymphocytes specifically adhere. This specific interaction can be studied in vitro by overlaying lymphocyte suspensions on cryostat sections of l...
Article
Full-text available
Occlusion of the afferent lymph flow to the lymph node (LN) results in both flattening of the endothelium of high endothelial venules (HEV) and a severe decrease in numbers of lymphocytes in transit across the walls of the flattened HEV. In the present study we have used the in vitro lymphocyte-binding assay to investigate the ability of HEV in rat...
Article
Lipofuscin is considered to be undigestible material present in secondary lysosomes. During histological and electron microscopical studies lipofuscin was observed in macrophages in popliteal lymph nodes in 3-6 month-old-male Wistar rats after occlusion of the afferent lymph flow to the lymph node. No pathological alterations were found in the lymp...
Article
Full-text available
The distribution and morphology of cells with surface and cytoplasmic immunoglobulins were investigated in mesenteric lymph nodes (MLN) from rats, using both frozen and (fixed) paraffin sections, with a two-step immunoperoxidase technique. Anti-IgA, -IgE, -IgG and -IgM sera were used. Surface Ig-cells (sIg) of all four isotypes studied were found i...