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1.
Cancer Res ; 61(18): 6925-30, 2001 Sep 15.
Article in English | MEDLINE | ID: mdl-11559571

ABSTRACT

A self-deleting retrovirus vector carrying a herpes simplex virus (HSV)-thymidine kinase suicide gene has been developed to selectively kill cancer cells expressing a dysfunctional p53 tumor suppressor protein. When cells containing functional p53 are infected with the virus, the integrated provirus and the HSV-thymidine kinase gene are deleted from the genome by site-specific recombination (Cre/loxP). In contrast, cells without p53 or cells expressing a DNA-binding mutant of p53 retain the provirus and become susceptible to killing by ganciclovir. This strategy provides a new concept for the selective killing of cancer cells that can be adapted to any other dysfunctional transcription factor expressed by different tumors.


Subject(s)
Genetic Therapy/methods , Retroviridae/genetics , Tumor Suppressor Protein p53/deficiency , Animals , Female , Ganciclovir/pharmacokinetics , Ganciclovir/pharmacology , Genetic Vectors/genetics , Humans , Mice , Mice, Nude , Proviruses/genetics , Simplexvirus/enzymology , Simplexvirus/genetics , Thymidine Kinase/genetics , Thymidine Kinase/metabolism , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology , Virus Integration/genetics , Xenograft Model Antitumor Assays
2.
Pharm Res ; 18(6): 771-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11474780

ABSTRACT

PURPOSE: To study the pulmonary absorption and tolerability of various formulations of the decapeptide cetrorelix acetate in rats by a new aerosol delivery system (ASTA-ADS) for intratracheal application. METHODS: Using the ASTA-ADS, cetrorelix liquid formulations (aqueous solutions for ultrasonic nebulization) were firstly selected and subsequently delivered as nebulized aerosol to orotracheally cannulated rats. The pharmacologic effect (decrease of testosterone serum level) of four cetrorelix formulations was determined in rats by enzyme linked immunosorbant assay, and pharmacokinetic data were determined after measurement of cetrorelix serum level by radioimmunoassay. Histological examination of the lung was performed at the end of the experiments, and in a supplementary experiment the respiratory parameters (resistance and compliance) of rats were monitored by a validated pulmonary monitoring system during the aerosol application of the same formulations. RESULTS: After an exposure time of 5 min, the applied formulations reduced the testosterone concentration in serum to subnormal levels (< or =1 ng/ml) over a period of 24 h. Comparing the plasma concentration after intratracheal aerosolization with data of intravenous administration, the mean calculated bioavailabilities for the four formulations using the corrected dose (delivered--exhaled amount) were between 48.4 +/- 27.0% and 77.4 +/- 44.0%. The histologic examination of the lungs revealed different tolerability of the various tested formulations ranging from locally intolerable to well tolerated. The measurement of the lung function parameters did not reveal any compound or formulation related changes. CONCLUSIONS: Our studies show that cetrorelix can be effectively administered as aerosol and that intratracheal aerosolization via the ASTA-ADS provides results that are well comparable to other application routes, as demonstrated by statistical comparison of the newly obtained data with previous results from intratracheal instillation of cetrorelix solutions in rats.


Subject(s)
Drug Delivery Systems/methods , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/administration & dosage , Hormone Antagonists/administration & dosage , Lung/drug effects , Administration, Inhalation , Animals , Drug Delivery Systems/instrumentation , Gonadotropin-Releasing Hormone/pharmacokinetics , Hormone Antagonists/pharmacokinetics , Intubation, Intratracheal , Lung/metabolism , Lung/physiopathology , Male , Rats , Rats, Sprague-Dawley , Respiratory Function Tests , Testosterone/antagonists & inhibitors , Testosterone/blood
3.
Lab Anim ; 35(3): 257-60, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11459411

ABSTRACT

As reported in the literature, oral endotracheal intubation of rats is considered to be very difficult. Specialised equipment and complicated techniques have been described to perform this procedure. In our experiment we adopted a simple method, which allowed-without any complicated equipment-the insertion of a relatively wide tube into the trachea of rats, allowing drug administration.


Subject(s)
Drug Delivery Systems/veterinary , Intubation, Intratracheal/veterinary , Administration, Inhalation , Administration, Oral , Aerosols , Animals , Intubation, Intratracheal/methods , Male , Rats , Rats, Sprague-Dawley
4.
Lab Anim ; 35(3): 261-70, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11459412

ABSTRACT

Over the last decade, the systemic absorption of a broad range of therapeutics after pulmonary application has been demonstrated in animals as well as in humans. The most common method used in the laboratory is the intratracheal instillation of drugs in solution. This method is, however, unsatisfactory, because of discrepancies in particle distribution, clearance, kind of injury and bioavailability between instillation and inhalative application. On the other hand, a precise determination of the amount of drug applied by aerosol, and of the aerosol volume retained within the lungs is rather difficult, and is not possible for use with small animals such as mice or rats. We describe a system which allows the delivery of aerosols directly into the animal's lungs, and calculation of the amount of drug retained in the lungs. Our system was tested in vitro and in vivo and was shown to allow precise and efficient pharmacokinetic and toxicological studies to be carried out.


Subject(s)
Drug Delivery Systems/veterinary , Intubation, Intratracheal/veterinary , Lung/drug effects , Absorption , Administration, Inhalation , Aerosols , Animals , Biological Availability , Intubation, Intratracheal/methods , Male , Rats , Rats, Sprague-Dawley
5.
Stem Cells ; 19(4): 313-20, 2001.
Article in English | MEDLINE | ID: mdl-11463951

ABSTRACT

In umbilical cord blood (UCB) transplantation, the number of nucleated cells per kilogram is a major predictive and critical factor of hematopoietic recovery. Thus, ex vivo expansion of hematopoietic UCB progenitors could potentially accelerate engraftment. Whereas Flt-3 ligand (FL), stem cell factor (SCF), and thrombopoietin (TPO) are considered indispensable, the role of interleukin 3 (IL-3) is still controversial: it has been reported either to support or abrogate the reconstituting ability of stem cells. By adding IL-3 we aimed to enhance the amplification of early and committed progenitor cells without impairing the long-term engraftment of stem cells. Demonstrating a positive impact of IL-3 on the proliferation of all progenitor subsets, the amplification of CD34+ UCB cells was increased 20.9-fold +/- 5.4 (mean +/- standard error) in serum-free culture with FL, SCF, TPO, and IL-3 as opposed to 9.3-fold +/- 3.2 without IL-3 after 7 days. If IL-3 was included, primitive long-term culture-initiating cells and committed colony-forming cells were expanded 16.3-fold +/- 5.5 and 18.1-fold +/- 2.4, respectively, compared to 12.6-fold +/- 5.6 and 9.1-fold +/- 2.0 without IL-3. Analysis of cultured CD34+ UCB cells in sublethally irradiated nonobese diabetic/severe combined immunodeficient mice confirmed that cultured cells had preserved their repopulating potential. After 6 weeks, all mice showed multilineage engraftment with their bone marrow containing an average of 45% human CD45+ cells of the unmanipulated sample, 43% of cells after culture in the presence of IL-3, and 27% of cells after culture without IL-3. In combination with early acting cytokines, IL-3 therefore improves the ex vivo expansion of UCB stem and progenitor cells without impairing their engraftment potential.


Subject(s)
Fetal Blood/cytology , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/physiology , Interleukin-3/pharmacology , Animals , Antigens, CD34/metabolism , Cell Division , Cell Separation , Cells, Cultured , Culture Media , Flow Cytometry , Hematopoietic Stem Cells/drug effects , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Receptors, CXCR4/metabolism
6.
Cancer Res ; 61(1): 392-9, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11196193

ABSTRACT

N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid (D-24851) is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. D-24851 destabilizes microtubules and blocks cell cycle transition specifically at G2-M phase. The binding site of D-24851 does not overlap with the tubulin binding sites of known microtubule-destabilizing agents like vincristine or colchicine. In vitro, D-24851 has potent cytotoxic activity toward a panel of established human tumor cell lines including SKOV3 ovarian cancer, U87 glioblastoma, and ASPC-1 pancreatic cancer cells. In vivo, oral D-24851 treatment induced complete tumor regressions (cures) in rats bearing Yoshida AH13 sarcomas. Of importance is that the administration of curative doses of D-24851 to the animals revealed no systemic toxicity in terms of body weight loss and neurotoxicity in contrast to the administration of paclitaxel or vincristine. Interestingly, multidrug-resistant cell lines generated by vincristine-driven selection or transfection with the Mr 170,000 P-glycoprotein encoding cDNA were rendered resistant toward paclitaxel, vincristine, or doxorubicin but not towards D-24851 when compared with the parental cells. Because of its synthetic nature, its oral applicability, its potent in vitro and in vivo antitumoral activity, its efficacy against multidrug-resistant tumors, and the lack of neurotoxicity, D-24851 may have significant potential for the treatment of various malignancies.


Subject(s)
Acetamides/pharmacology , Antineoplastic Agents/pharmacology , Indoles/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Acetamides/metabolism , Acetamides/toxicity , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Binding Sites , Binding, Competitive , Cell Cycle/drug effects , Cell Division/drug effects , Colchicine/metabolism , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Humans , Indoles/metabolism , Indoles/toxicity , Microtubules/drug effects , Motor Activity/drug effects , Multidrug Resistance-Associated Proteins , Nervous System Diseases/chemically induced , Neural Conduction/drug effects , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sarcoma, Yoshida/drug therapy , Tubulin/metabolism , Tumor Cells, Cultured/drug effects , Vincristine/metabolism
7.
Mol Biochem Parasitol ; 111(1): 1-14, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11087912

ABSTRACT

Ether-lipid (alkyl-phospholipid) analogues such as Miltefosine possess potent in vitro and in vivo anti-leishmanial activity and these compounds are currently undergoing clinical trials in humans. These analogues are also effective against Trypanosoma cruzi and Trypanosoma brucei subspecies but their mode of action is not known. Leishmania have high levels of ether-lipids and these are mainly found in the glycosylphosphatidylinositol-anchored glycolipids and glycoproteins present on the surface of the parasites. In Leishmania mexicana promastigotes we have studied both the initiating steps for the biosynthesis of ether-lipids, and key remodelling steps. The effect of Miltefosine and Edelfosine, on key enzymes involved in the metabolism of ether-lipids has been studied. The enzymes include dihydroxyacetonephosphate acyltransferase, sn-l-acyl-2-lyso-glycero-3-phosphocholine and sn-l-alkyl-2-lyso-glycero-3-phosphocholine acyltransferases. We confirm that the initiating steps in ether-lipid metabolism in Leishmania are present in glycosomes, and that Miltefosine or Edelfosine did not perturb these enzymes. The metabolism of the latter phosphatidylcholine base intermediates, which may be involved in the remodelling of acyl- and alkyl-glycerophospholipids, was also seemingly associated with glycosomes. Both Miltefosine and Edelfosine inhibited this microbody (glycosomal) located alkyl-specific-acyl-CoA acyltransferase in a dose-dependent manner with an inhibitory concentration of 50 microM. It is suggested therefore that a perturbation of ether-lipid remodelling could be responsible for the anti-leishmanial action of these drugs.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania mexicana/metabolism , Phospholipid Ethers/metabolism , Phospholipid Ethers/pharmacology , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacology , Acylation , Acyltransferases/antagonists & inhibitors , Acyltransferases/metabolism , Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/metabolism , Alkyl and Aryl Transferases/antagonists & inhibitors , Alkyl and Aryl Transferases/metabolism , Animals , Leishmania mexicana/drug effects , Leishmania mexicana/enzymology , Microbodies/metabolism
8.
Eur J Pharm Sci ; 9(3): 253-8, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10594381

ABSTRACT

Pulmonary absorption of the decapeptide cetrorelix acetate was studied in rats by a non-surgical intratracheal instillation method. The pharmacological effect (decrease of testosterone plasma concentration) following intratracheal (i.t.) instillation was determined in four groups of seven rats each at three different concentrations (0.5, 1.0 and 2.5 mg/kg body weight). The applied doses reduced testosterone plasma concentration to subnormal level (

Subject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Hormone Antagonists/administration & dosage , Testosterone/blood , Animals , Area Under Curve , Gonadotropin-Releasing Hormone/administration & dosage , Gonadotropin-Releasing Hormone/pharmacokinetics , Gonadotropin-Releasing Hormone/pharmacology , Hormone Antagonists/pharmacokinetics , Hormone Antagonists/pharmacology , Instillation, Drug , Intubation, Intratracheal , Male , Rats , Rats, Sprague-Dawley , Tissue Distribution
9.
Trans R Soc Trop Med Hyg ; 93(1): 85-90, 1999.
Article in English | MEDLINE | ID: mdl-10492799

ABSTRACT

Ether-lipids and alkylphosphocholines have been found to have anti-leishmanial activity. Oral treatment with hexadecylphosphocholine (HePC) efficiently reduces parasite burden in murine visceral leishmaniasis. Drugs for the treatment of cutaneous leishmaniasis are most commonly administered parenterally, whereas efficient drugs for topical treatment are not in current use. Here we investigate the efficacy of topical treatment with HePC in mice infected with Leishmania mexicana or L. major, causative agents of cutaneous leishmaniasis in the New and Old World, respectively. BALB/c, CBA/J and C57BL/6 inbred mice do not control infection with L. mexicana because they do not mount an efficient Th1-type anti-parasitic lymphocyte response. In contrast, C57BL/6 mice are resistant to an infection with L. major, developing only transient lesions that heal spontaneously owing to an efficient Th1 response. BALB/c, CBA/J and C57BL/6 mice were infected subcutaneously with L. mexicana amastigotes, causing nodular lesions after 5 months. Topical treatment with HePC (Miltex) was highly effective in reducing parasite burden and healed established lesions. The treatment did not induce a Th1 response in L. mexicana-infected susceptible mice and most of the mice relapsed. In resistant C57BL/6 mice infected subcutaneously with 2 x 10(6) L. major promastigotes at the tail base, nodular lesions developed after 2 weeks. Topical treatment with Miltex reduced the parasite load and the mice healed their lesions much faster than the untreated infected controls. The clinical application of Miltex for treatment of cutaneous leishmaniasis may be highly efficient because humans, similarly to resistant mice, in general do not relapse after healing. Clinical trials should be straightforward considering that Miltex is an approved drug for the treatment of breast cancer metastases.


Subject(s)
Antiprotozoal Agents/therapeutic use , Leishmaniasis, Cutaneous/drug therapy , Phosphorylcholine/analogs & derivatives , Administration, Topical , Animals , CD4-Positive T-Lymphocytes/parasitology , Drug Evaluation, Preclinical , Female , Leishmania mexicana/isolation & purification , Leishmaniasis, Cutaneous/parasitology , Lymphatic Diseases/parasitology , Mice , Mice, Inbred Strains , Phosphorylcholine/therapeutic use
10.
Eur J Cancer ; 33(3): 442-6, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9155530

ABSTRACT

The aim of this study was to determine the antitumour effects of D-21266 in a rodent tumour model. Hexadecylphosphocholine (INN: Miltefosine) represents the first anticancer agent which was specifically formulated for topical use in cancer patients. The development as an oral drug was hampered by the gastrointestinal toxicity. Hexadecylphosphocholine derivatives were sought with a better therapeutic index. Octadecyl-(1,1-dimethyl-4-piperidylio) phosphate (D-21266) was identified as a suitable candidate. This compound is highly active in vitro inhibiting the growth of a number of human cancer cell lines. Mammary carcinomas were induced in Sprague-Dawley rats using DMBA, and oral doses of D-21266, in various schedules, were given to the animals. A high antineoplastic potency was observed without inducing loss of body weight at highly effective doses. The antitumour effect could be enhanced by introducing a dose schedule consisting of a high loading dose followed by a low maintenance dose, both of which are only marginally active when given alone. Therefore, D-21266 with its favourable pharmacological and toxicological profile, warrants evaluation in the clinic. However, the concept of clinical trials requires new approaches to dose finding and response evaluation, because the dose-response relationship of this compound is distinctly different from that of classical cytostatic agents.


Subject(s)
Antineoplastic Agents/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Phosphorylcholine/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Female , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/pathology , Phosphorylcholine/pharmacology , Phosphorylcholine/therapeutic use , Rats , Rats, Sprague-Dawley , Tumor Cells, Cultured/drug effects
11.
J Pharm Sci ; 86(3): 283-9, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9050794

ABSTRACT

The biological effects of bisphosphonates in calcium-related disorders are attributed to the incorporation of the bisphosphonates in bone, enabling direct interaction with osteoclasts and/or osteoblasts. The high accumulation of bisphosphonates in bone, due to their high affinity to hydroxyapatite (HAP), is essential for mediating in vitro and in vivo activity. In this study we examined the activity of tetrakisphosphonates, molecules containing two P-C-P type bisphosphonate moieties connected by a carbon chain. The novel compounds were examined in a battery of in vitro and in vivo models including HAP formation and dissolution, ectopic calcification, bone resorption, tumor osteolysis, and of macrophage-like cells (anti- or pro-inflammatory properties). The inhibition of ectopic calcification was ranked as follows: geminal bisphosphonates > bisacylphosphonates > tetrakisphosphonates. Pamidronate, but not the tetrakisphosphonates, was an effective antiosteolytic agent. Neither DNTP (tetrasodium 1,9-dihydroxynonane 1,1,9,9-tetrakisphosphonate) nor the bisacylphosphonate, PiBP (pimeloylbisphosphonate) seem to possess strong macrophage suppressive or inductive effects and can be considered to be relatively inactive in terms of anti- or pro-inflammatory action. A significant anticalcification effect was caused by various phosphonates, such as the tetrakisphosphonates, but DNTP, a tetrakisphosphonate, was found toxic as it impeded somatic growth and bone development.


Subject(s)
Bone Resorption/chemically induced , Calcinosis/prevention & control , Carcinoma 256, Walker/drug therapy , Diphosphonates/pharmacology , Osteolysis/prevention & control , Animals , Bioprosthesis , Calcinosis/pathology , Carcinoma 256, Walker/pathology , Cell Line , Cell Survival/drug effects , Diphosphonates/chemical synthesis , Diphosphonates/toxicity , Durapatite/chemistry , Etidronic Acid/pharmacology , Female , Macrophages/drug effects , Mice , Osteolysis/pathology , Pamidronate , Rats , Rats, Wistar
12.
Oncogene ; 13(5): 901-11, 1996 Sep 05.
Article in English | MEDLINE | ID: mdl-8806679

ABSTRACT

In the present study we describe the reversible transformation of NIH3T3 fibroblasts by overexpression of the HER2/c-erbB2 receptor tyrosine kinase. Cell lines expressing HER2 under control of a tetracycline-responsive promoter were isolated. Induction of HER2 expression resulted in cellular transformation in vitro as depicted by growth in soft agar and focus formation in tissue culture. Subsequent treatment of these cells with the effector anhydrotetracyline switched-off HER2 expression and induced morphological and functional changes characteristic for non-transformed cells. Subcutaneous transplantation of cells in nude mice resulted in the formation of solid tumors. Interestingly tumor formation was completely suppressed by treatment of the animals with anhydrotetracyline. Our findings indicate that overexpression of HER2 induces the transformed phenotype of NIH3T3 cells and is required for tumor formation and progression in nude mice. By linking the expression of the marker gene secreted placental alkaline phosphatase to the expression of HER2, a sensitive monitoring of tumor development in nude mice was feasible.


Subject(s)
Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/genetics , Receptor, ErbB-2/biosynthesis , 3T3 Cells , Alkaline Phosphatase/genetics , Alkaline Phosphatase/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Transformed , Female , Gene Expression Regulation, Neoplastic , Mice , Mice, Nude , Neoplasms, Experimental/drug therapy , Phenotype , Receptor, ErbB-2/genetics , Repressor Proteins/genetics , Tetracycline/pharmacology , Tetracyclines/pharmacology , Trans-Activators/genetics , Transcription, Genetic , Transplantation, Heterologous
13.
Eur J Cancer ; 32A(9): 1574-9, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8911120

ABSTRACT

The antitumour and hormone-suppressive effects of the luteinising hormone-releasing hormone LH-RH antagonist Cetrorelix (D-20761) and its pamoate salt (D-20762) were investigated in the model of the DMBA-induced mammary carcinoma of female rats and by testosterone determinations in normal male rats. Treatment with single high doses of D-20761 induced a rapid decrease of tumour weights with a dose-dependent duration of action. Strong antitumour effects were also observed by applying different multiple dose schedules, including a initial high dose (3.16 mg/kg, s.c.) followed by a low maintenance dose (31.6 micrograms/kg, s.c.). The stability of the molecule against degrading enzymes led to the idea of using the poorly soluble pamoate salt for facilitating a sustained release of active compound. This salt indeed induced a prolonged suppression of tumour growth and of testosterone levels. In conclusion, we found that Cetrorelix is a highly effective LH-RH antagonist which should be further developed for the treatment of hormone-dependent diseases.


Subject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Mammary Neoplasms, Experimental/drug therapy , Animals , Dose-Response Relationship, Drug , Female , Gonadotropin-Releasing Hormone/blood , Gonadotropin-Releasing Hormone/chemistry , Gonadotropin-Releasing Hormone/pharmacology , Gonadotropin-Releasing Hormone/therapeutic use , Male , Peptide Hydrolases/physiology , Rats , Rats, Sprague-Dawley , Testosterone/analysis
17.
Eur J Cancer ; 31A(3): 372-4, 1995.
Article in English | MEDLINE | ID: mdl-7786605

ABSTRACT

The effect of pretreatment with miltefosine (MIL) on the antineoplastic activity of cyclophosphamide (CPA) was evaluated in subcutaneous benzo(a)pyrene-induced sarcomas (BPS) of the rat. MIL alone had no antineoplastic effect on this autochthonous tumour, but enhanced the chemotherapeutic effect of CPA. Conversely, MIL counteracted the myelotoxicity of CPA in normal adult rats. Although the nadir of the leucocyte count remained unchanged, the recovery phase was considerably shortened, an effect which resembled the pharmacological action of GM-CSF.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukopenia/chemically induced , Sarcoma, Experimental/drug therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzo(a)pyrene , Cyclophosphamide/administration & dosage , Cyclophosphamide/antagonists & inhibitors , Cyclophosphamide/toxicity , Female , Leukocyte Count/drug effects , Phosphorylcholine/administration & dosage , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacology , Rats , Rats, Sprague-Dawley , Sarcoma, Experimental/chemically induced , Sarcoma, Experimental/pathology
18.
Nucl Med Biol ; 21(6): 835-45, 1994 Aug.
Article in English | MEDLINE | ID: mdl-9234333

ABSTRACT

Two cell lines derived from a lung metastasis of a rat osteosarcoma were treated with cisplatin (CDDP) and two phosphonic acid compounds (AMDP, DADP), AMDP-treated cells showed a decrease in FDG uptake, CDDP and DADP resulted in an increase. A block in G2 or in S and G2 phase was seen after CDDP and AMDP treatment. The changes in the cell cycle fractions were not related to the changes in FDG uptake. Furthermore, the transcription of the glucose transporter and hexokinase genes were elevated in CDDP and decreased in AMDP treated cells. However, the changes in FDG uptake were not fully explained by changes at the transcriptional level. The total uptake of thymidine was elevated although the incorporation of thymidine into DNA decreased. In both cell lines the changes in FDG uptake correlated with the changes in thymidine incorporation into DNA (r = 0.95 and r = 0.83, respectively). Cells with an increased FDG uptake showed a weaker growth inhibition than cells with a decrease in FDG uptake.


Subject(s)
Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Cisplatin/therapeutic use , Lung Neoplasms/metabolism , Osteosarcoma/drug therapy , Transcription, Genetic/drug effects , Animals , Antineoplastic Agents/pharmacology , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Cisplatin/pharmacology , Deoxyglucose/analogs & derivatives , Deoxyglucose/metabolism , Flow Cytometry , Fluorodeoxyglucose F18 , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/therapeutic use , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Osteosarcoma/genetics , Osteosarcoma/metabolism , Rats , Thymidine/metabolism
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