Trace Elements In The Treatment Of Cancer






Press Releases Newsletter

Parker Hughes Institute scientists develop 24 new drugs containing metal

Vanadium effective in fighting cancer cells

May 3, 2000, Saint Paul, Minn. ( In a systematic effort to develop effective drugs with a broad spectrum and potent anti-cancer activity, researchers at the St. Paul, Minn.-based Parker Hughes Institute have developed 24 new drugs containing the metal vanadium. The results of this research are published in this monthÕs issue of Clinical Cancer Research, the official scientific journal of the American Association of Cancer Research.

These novel drugs were effective against 14 of 14 different cancer cell lines as well as cancer cells taken directly from patients. Targeted cancer cells included those of breast cancer, prostate cancer, testicular cancer, ovarian cancer, colon cancer, brain tumors, leukemia and lymphoma. These new anti-cancer drugs work by causing the cancer cells to commit suicide (or apoptosis) within 4 to 24 hours.

These drugs are now being tested in animal safety studies to identify those that have the best therapeutic index.

References Narla RK, Dong Y, DÕCruz OJ, Navara C, Uckun FM. Bis (4,7-dimethyl-1, 10-phenanthroline) sulfatooxovanadium as a novel apoptosis-inducing anticancer agent. Clinical Cancer Research, 6:1546-56, 2000.

Ghosh P, DÕCruz OJ, Narla RK, Uckun FM. Apoptosis-inducing vanadocene compounds against human testicular cancer. Clinical Cancer Research, 6:1536-45, 2000.

The Parker Hughes Institute http://www.parkerughes.org/, located in Roseville, Minnesota, is a non-profit research organization dedicated to combating cancer, AIDS, and diseases of the immune system.






Press Releases Newsletter

New agents show potential for treatment of testicular cancer

August 10, 2000, St. Paul, MN...Studies conducted at Parker Hughes Institute involving vanadium-containing agents called "vanadocene" show potential for treating testicular cancer. The results of this work are published in this month's issue of Toxicology and Applied Pharmacology.

This agent was previously found to have powerful sperm immobilizing activity, prompting scientists to conduct further research. The present study establishes that vanadocenes are cytotoxic and induce cell death of testicular cancer cells.

Testicular cancer develops in one or both testicles in men or young boys. The American Cancer Society estimates that in the year 2000 about 6,900 new cases of testicular cancer will be diagnosed in the United States. While testicular cancer is a highly treatable and usually curable form of cancer, an estimated 300 men will die of testicular cancer in this year.

Over 90% of cancers of the testicle develop in certain cells known as germ cells. Most invasive testicular germ cell cancers begin as a noninvasive form of the disease called carcinoma in situ (CIS) or intratubular germ cell neoplasia. Researchers have estimated that it takes approximately five years for CIS to progress to the invasive form of germ cell cancer. When a cancer becomes invasive, its cells have penetrated the surrounding tissues and may have spread through either the blood circulation or the lymph nodes to other parts of the body.

Vanadocenes have the ability to induce selective cytotoxicity and cell death of testicular germ cells. "We are very excited about the potential of vanadocenes to target germ cells," said Dr. Osmond D'Cruz, director, department of reproductive biology, Parker Hughes Institute, and lead author on the study. "This knowledge provides the basis for evaluation of vanadocenes as less-toxic alternatives to currently available treatments for testicular cancer."

Reference: D'Cruz OJ, Uckun FM. Vanadocene-Mediated in Vivo Male Germ Cell Apoptosis. Toxicology and Applied Pharmacology, 166(3):186-95, 2000.

The Parker Hughes Institute http://www.parkerhughes.org/, located in St. Paul, Minnesota, is a non-profit research organization dedicated to eradicating cancer, AIDS, and diseases of the immune system.

Vanadium prevention of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis: probable involvement of representative hepatic phase I and II xenobiotic metabolizing enzymes.

Bishayee A, Oinam S, Basu M, Chatterjee M.

Department of Pharmaceutical Technology, Jadavpur University, Calcutta, India. bishayan@umdnj.edu

Vanadium, a non-platinum group metal and dietary micronutrient, is now proving to act as a promising antitumor agent. The present study was conducted to ascertain its antineoplastic potential against an experimental mammary carcinogenesis. Female Sprague-Dawley rats, at 50 days of age, were treated with 7,12-dimethylbenz(a)anthracene (DMBA) (0.5 mg/100 g body weight) by a single tail vein injection in an oil emulsion. Vanadium (ammonium monovanadate) at the concentration of 0.5 ppm was supplemented in drinking water and given ad libitum to the experimental group immediately after the carcinogen treatment and it continued until the termination of the study (24 weeks for histological and biochemical observations and 35 weeks for morphological findings). It was found that vanadium treatment brought about a substantial protection against DMBA-induced mammary carcinogenesis. This was evident from histological findings that showed no sign of hyperplasia or abnormality after vanadium treatment. There was a significant reduction in incidence (P < 0.05), total number, multiplicity (P < 0.01) and size of palpable mammary tumors and delay in mean latency period of tumor appearance (P < 0.001) following vanadium supplementation compared to DMBA control. From the cumulative results of various hepatic biochemical indices namely, lipid peroxidation, reduced glutathione level, superoxide dismutase activity, cytochrome P450 content and glutathione S-transferase activity, the anticarcinogenic potential of vanadium was well reflected through stabilization of these parameters. Results of the study indicate that the anticarcinogenic activity of vanadium during DMBA-initiated mammary carcinogenesis is mediated through alteration of hepatic antioxidant status as well as modulation of phase I and II drug metabolizing enzymes. On the basis of the observed results, vanadium can be considered as a readily available, promising and novel cancer chemopreventive agent.

PMID: 11097089 [PubMed - indexed for MEDLINE]

Antitumour metallocenes: structure-activity studies and interactions with biomolecules.

Harding MM, Mokdsi G.

School of Chemistry, University of Sydney, N.S.W., New South Wales, 2006, Australia. harding@chem.usyd.edu.au

The metallocene dihalides are a relatively new class of small, hydrophobic organometallic anticancer agents that exhibit antitumour properties against numerous cell lines including leukemias P388 and L1210, colon 38 and Lewis lung carcinomas, B16 melanoma, solid and fluid Ehrlich ascites tumours and several human colon and lung carcinomas transplanted into athymic mice. Titanocene dichloride 1 has been the most widely studied metallocene and the drug is currently in phase II clinical trials. Formation of metallocene-DNA complexes has been implicated in the mechanism of antitumour properties of the metallocenes, as both titanocene dichloride 1 and vanadocene dichloride 2 inhibit DNA and RNA synthesis, and titanium and vanadium accumulate in nucleic acid-rich regions of tumour cells. However, in contrast to the well characterized platinum-based anticancer drugs, the active species responsible for antitumour activity in vivo has not been identified and the mechanism whereby irreparable DNA damage and/or structural modification of DNA or other cellular targets occurs is poorly understood. This review will focus on recent studies that have been carried out in order to identify the biologically active species and more fully understand the molecular level mechanism of action of the metallocene dihalides. Studies with nucleotides, oligonucleotides, DNA and proteins including topoisomerases, protein kinase C and transferrin have provided important insight into potential cellular transport mechanisms and the interaction of metallocenes with biomolecular targets. New structure activity studies including the design of hydrolytically stable metallocenes and the preparation of highly water soluble amino acid analogues have not led to improved anticancer activity of titanocene dichloride 1. The vastly different chemical and hydrolytic stability of each of the metallocenes points to a unique mechanism of action of each metallocene in vivo.

Publication Types:

Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.

Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, Slate EH, Witherington R, Herlong JH, Janosko E, Carpenter D, Borosso C, Falk S, Rounder J.

Arizona Cancer Center, College of Medicine, University of Arizona, Tucson 85716, USA.

OBJECTIVE: To test if supplemental dietary selenium is associated with changes in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.

Publication Types:

Effects of silica on human lung fibroblast in culture.

Arcangeli G, Cupelli V, Giuliano G.

Istituto di Medicina del Lavoro-Largo P.Palagi 1, Firenze, Italy. argiulio@flownet.it

Silica has been reported to directly stimulate cellular proliferation of human lung fibroblasts, and silica-treated macrophage supernatants induce fibroblast proliferation and some of their biosynthetic activities. Alveolar macrophages produce increased amount of tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta). Lung fibroblasts are producers of interleukin-6 (IL-6). We investigated the capacity of lung fibroblasts obtained from normal and silicosis subjects to elaborate IL-6 in response to TNF-alpha and to TGF-beta. Our data show that TNF-alpha and TGF-beta are able to stimulate the proliferation of human lung fibroblasts in culture, to increase the collagen production of the cells and are both able to increase IL-6 production by lung fibroblasts of patients with silicosis. We hypothesise that silica is able to stimulate lung fibroblast both directly, increasing the cell proliferation, and indirectly stimulating the release of factors (as TNF-alpha and TGF-beta) from activated alveolar macrophages, that are able to increase proliferative and biosynthetic activities of fibroblast.

PMID: 11327386 [PubMed - indexed for MEDLINE]

[Platinum compounds in cancer therapy--past, present, and future].

[Article in Japanese]

Akaza H, Saijo N, Aiba K, Isonishi S, Ohashi Y, Kawai K, Konishi T, Saeki T, Sone S, Tsukagoshi S, Tsuruo T, Noguchi S, Miki T, Mikami O, Smith M, Hoctin-Boes G, Stribling D.

Dept. of Urology, Institute of Clinical Medicine, University of Tsukuba.

Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents have been widely used in both registered and non registered indications and are frequently combined with other cytotoxics. In Japan, cisplatin has been used successfully at low doses in combination with 5-FU based regimens and appears to achieve a synergistic effect, but controlled data are not yet available. More recently oxaliplatin (Europe) and nedaplatin (in Japan) have been introduced, but their clinical roles in therapy have yet to be established. One of the limiting features of the first generation of platinum compounds is that a significant proportion of tumours develop cross resistance to platins due to either changes in uptake or excretion, intracellular detoxification or accelerated DNA repair. The forum discussed the possibility for the development of better new platinum compounds, A new platin agent which had lower toxicity and higher efficacy across a wide range of cancers without the development of resistance would be a significant step forward. If the tolerability profile was suitable, an oral formulation may improve the quality of life for patients but this must not be at the expense of efficacy. Even after the introduction of new target based drugs, platinum cytotoxics are likely to be used to reduce the tumour mass and in some cases can be expected to potentiate the effects of the new agents. In preclinical studies, ZD0473 has been shown to by-pass some major mechanisms of resistance and has the potential to achieve these objectives and is now being evaluated in clinical studies in both Japan and the West.

Publication Types:

Validation of an AAS method for the determination of platinum in biological fluids from patients receiving the oral platinum derivative JM216.

Vouillamoz-Lorenz S, Bauer J, Lejeune F, Decosterd LA.

Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland

A flameless atomic absorption spectrometric (AAS) method has been developed and validated for the determination of platinum (Pt) in human plasma, plasma ultrafitrate and urines from cancer patients receiving the orally available platinum derivative, JM216. Sample pretreatment is minimal for urine, which is diluted with 10% HCl prior to AAS analysis. Pt analysis in plasma requires the application of the matrix modifier 5% Triton X-100 directly onto the integrated L'vov platform of the graphite furnace prior to the addition of plasma samples. For Pt in ultrafiltrates, enhanced sensitivity is achieved by pre-concentrating ultrafiltrate samples onto the platform prior to the ashing/atomisation step. The AAS program was set specifically for each considered matrix enabling to achieve limit of quantitations as low as 50, 10 and 5 ng Pt ml(-1) for urine, plasma and plasma ultrafiltrate, respectively. The calibration was linear (r(2)>0.993) over the working range 5-150 ng Pt ml(-1). The method has been validated according to the Recommendations on Bioanalytical Methods Validation. The stability of Pt in samples has been explored, as well as the specificity of the method. In the urine intra-assay precision of control samples at 60, 90 and 140 ng Pt ml(-1) is always lower than 3.0, 1.3 and 4.7%, respectively, with concentrations not deviating more than -5.5 to -1.0% from their nominal values, while inter-assay precision is within 5.7-7.7% and inter-assay deviation within the -1.9 to +4.3% range. Intra-assay precision of plasma control samples at 20, 70 and 140 ng Pt ml(-1) is always lower than 8% and concentrations never deviating more than 7.1% from their nominal values. Inter-assay precision of plasma control samples is always lower than 9% with inter-assay deviation from their nominal concentrations within the -3.9 to +1.8% range. In plasma ultrafiltrate, intra-assay CVs of control samples at 12, 25 and 45 ng Pt ml(-1) are always lower than 2.6, 1.7 and 6.8%, respectively, with concentrations not deviating more than -2.6 to -0.2% from their nominal values, while inter-assay CVs are within 5.1-9.5% and inter-assay deviation within the -1.6 to +5.3% range. The proposed method has, therefore, the required performance to measure Pt in biological samples and has been successfully applied to the determination of Pt in samples from cancer patients receiving JM216 in a phase I (daily administration for 14 days, dose escalation 10-50 mg m(-2)) and a phase II (fixed dose 120 mg m(-2) over 5 days) clinical study. In phase I study, both total and ultrafiltrable Pt accumulated upon repetitive dosings, showed long elimination half-lives (t(1/2)) and were measurable 2 weeks after the end of JM216 administration.

PMID: 11377026 [PubMed - in process]Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(I.V.) as a novel antileukemic agent with matrix metalloproteinase inhibitory activity.

Narla RK, Dong Y, Klis D, Uckun FM.

Parker Hughes Cancer Center, Drug Discovery Program, Department of Experimental, Parker Hughes Institute, St. Paul, Minnesota 55113, USA.

We have examined the in vitro anticancer activity of METVAN [bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(IV); VO(SO(4))(Me(2)-Phen)(2)] against acute lymphoblastic leukemia (ALL; NALM-6 and MOLT-3), acute myeloid leukemia (AML; HL-60), Hodgkin's disease (HS445), and multiple myeloma (ARH-77, U266BL, and HS-SULTAN) cell lines as well as primary leukemic cells from patients with ALL, AML, and chronic acute myeloid leukemia (CML). METVAN induced apoptosis in NALM-6, MOLT-3, and HL-60 cells in a concentration-dependent fashion with EC(50) values of 0.19 +/- 0.03 microM, 0.19 +/- 0.01 microM, and 1.1 +/- 0.2 microM, respectively. METVAN induced apoptosis at low micromolar concentrations in primary leukemic cells from patients with ALL, AML, and CML. METVAN inhibited the constitutive expression of matrix metalloproteinase (MMP)-9 protein and its gelatinolytic activity in HL-60 cells and MMP-2 as well as MMP-9 gelatinolytic activities in leukemic cells from ALL, AML, and CML patients. Furthermore, METVAN inhibited the leukemic cell adhesion to the extracellular matrix proteins laminin, type IV collagen, vitronectin, and fibronectin and the invasion through Matrigel matrix. Further preclinical development of METVAN may provide the basis for the development of more effective chemotherapy programs.

PMID: 11309362 [PubMed - indexed for MEDLINE]

Apoptosis inducing novel anti-leukemic agent, bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(iv).

Narla RK, Dong Y, Uckun FM.

Parker Hughes Cancer Center, Departments of Experimental Oncology and Chemistry, and Drug Discovery Program Parker Hughes Institute, St. Paul, Minnesota 55113, USA.

Bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(IV) [VO(SO(4) )(Me(2) -Phen)(2) ] induces apoptosis in human NALM-6 leukemia cells. In the present report, we demonstrate that VO(SO(4) )(Me(2) -Phen)(2) -induced apoptosis is mediated through the generation of reactive oxygen species (ROS), depletion of glutathione and depolarization of mitochondrial membrane potential (DeltaPsim). Using multilaser flow cytometry methods, we further mapped out the death sequence that occurs in VO(SO(4) )(Me(2) -Phen)(2) -treated leukemic cells. Triple labeling method to measure ROS, DeltaPsim and glutathione coupled with multilaser excitation flow cytometry showed that induction of ROS took place before the loss of mitochondrial permeability transition and depletion of glutathione. Correlated two parameter plots of glutathione content versus DeltaPsim showed that loss of DeltaPsim and depletion of glutathione closely follows each other. Translocation of phosphatidylserine to the outer leaflet of the cell membrane was the final step in the process before the cells became apoptotic. These results demonstrate that the mitochondrial permeability transition takes place during VO(SO(4) )(Me(2) -Phen)(2) -induced apoptosis and is mediated through induction of ROS and depletion of glutathione.

PMID: 11378580 [PubMed - in process]