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H R Hartmann

Publications and source records attributed to H R Hartmann.

14 recordsLinked to original sources
PubMed1990

Synthesis and antitumor activity of novel 4-demethoxyanthracyclines.

A versatile and efficient synthetic route to 4-demethoxyanthracyclinones has been utilized in the preparation of a number of aglycons having 9-alkyl, 9-(hydroxylalkyl), or 9-carbamoyl substituents. Silver trifluoromethanesulfonate catalyzed coupling of these aglycons with various daunosamine derivatives has yielded a series of novel anthracyclines which have been evaluated as antitumor agents. 9-Alkylanthracyclines 22, 23, 33, and 34 have higher efficacy vs L-1210 leukemia than the parent 4-demethoxydaunorubicin (21), or the natural anthracyclines daunorubicin (1) and doxorubicin (2). 9-(Hydroxyalkyl) derivatives have in most cases high efficacy but are slightly less potent than 21. 9-Methyl analogue 22 has higher efficacy vs P388 leukemia than other anthracyclines tested, while 9-(hydroxymethyl) derivative 37 retains similar efficacy to anthracyclines 1, 2, and 21 but is considerably more potent. The N-substituted 9-carbamoylanthracyclines are devoid of antitumor activity.

Animals↗
PubMed1990

Synthesis and antitumor activity of 9-[(carbamoyloxy)alkyl]anthracyclines: a novel class of anthracycline derivatives.

A number of 4-demethoxyanthracyclines having hydroxylalkyl functions at the 9-position have previously been synthesized and shown to have potent antitumor activity. A series of carbamate derivatives of these (hydroxyalkyl)anthracyclines have now been prepared, many of which possess considerably greater efficacy in an L-1210 leukemia test system than do the parent alcohols or the known anthracyclines daunorubicin (1), doxorubicin (2), and 4-demethoxydaunorubicin (3). Phenylcarbamate 8a was more active than methyl analogue 8b, while the 4'-deoxy and 4'-epi phenylcarbamates 17 and 18 showed particularly high efficacy at optimal dose levels similar to that of doxorubicin. Secondary carbamates were more potent, with the 13R isomer 23 having significantly higher efficacy than 13S analogue 24.

Animals↗
PubMed1987

Inhibition of rat mammary carcinogenesis by an arotinoid without a polar end group (Ro 15-0778).

The influence of an arotinoid without a polar end group (Ro 15-0778) on rat mammary carcinogenesis was investigated. Mammary tumors were induced by oral administration of 15 mg, 7,12-dimethylbenz-(a) anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Ro 15-0778 inhibited the development of mammary adenocarcinomas. The percentage of tumor-bearing rats, the mean number of tumors per rat as well as the mean total volume of tumors per rat were dose-dependently reduced by Ro 15-0778. The results are of particular interest, since this compound--probably because of the lack of a polar end group--does not induce the signs and symptoms of hypervitaminosis A. The inhibition of mammary cancer development by Ro 15-0778 compares favorably with that of N-(4-hydroxyphenyl) retinamide the hitherto most effective retinoid for prevention of chemically-induced mammary cancers in rats.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

[Liposomes as carriers of lipophilic cytosine arabinoside and fluorodeoxyuridine derivatives. Their cytostatic effect and possibilities of tumor cell specific therapy].

A method of preparation for large volumes of sterile, homogenous bilayer liposomes as carriers of lipophilic cytostatic prodrugs is described. Liposomes in the size range of 60 to 120 nanometers are produced through the dialysis of lipid/prodrug/detergent micelles by means of a capillary dialysis system. The cytostatic effect of cytosine arabinoside (ara-C) prodrug liposomes against L1210 leukemia showed to be superior to free ara-C treatment in respect to drug dosage and treatment schedule. Fluorodeoxyuridine (FUdR) prodrug-liposomes were active against various solid tumors, although with less pronounced effects, but at 20-60 times lower drug concentrations as compared to free FUdR. To further improve the cytostatic effect of such prodrug-containing liposomes, methods for the linkage of tumor-cell-specific antibodies to the liposomes are discussed. The targeted delivery of cytostatic drugs by such means might improve their antitumor effects and reduce the untoward toxic side-effects.

Animals↗
PubMed1986

Treatment of murine L1210 lymphoid leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes.

Lipophilic prodrugs of I-beta-D-arabinofuranosyl cytosine (Ara-C), namely N4- and 5'-oleyl-I-beta-D-arabinofuranosyl cytosine (N4-oleyl-ara-C, 5'-oleyl-ara-C) and N4-palmitoyl-I-beta-D-arabinofuranosyl cytosine (N4-palm-ara-C) were incorporated into liposomes of various lipid compositions. The phospholipid vesicles were prepared by controlled dialysis of lipid/prodrug/detergent micelles yielding homogeneous and stable unilamellar liposomes. The liposome size ranged from 70 to 120 nm depending on the lipid composition and the amounts of prodrug incorporated. Depending on the total amount of micellized Ara-C prodrugs, a maximal incorporation rate of 250 micrograms prodrug per mg egg phosphatidylcholine was achieved. The incorporation efficiency was in the range of 85 to 97%. The in vivo antitumor activity of the liposome preparations against L1210 lymphoid leukemia was clearly superior by factors of 2-8 depending on the therapy schedule and route of drug application. The treatment of melanoma B16 with free Ara-C as well as with the prodrug-liposomes exhibit rather weak antitumor activity. Drug application by means of prodrug-liposomes yields equal or higher tumor-inhibitory effects at drug concentrations which were 2-4 times lower than those of free Ara-C. Although drug tolerance and myelosuppression studies with Swiss albino mice revealed that the prodrug-liposomes were 5-10 times more toxic than free Ara-C, a substantial improvement of efficiency could be observed. The incorporation of the ara-C prodrugs into liposomes provides protection against fast degradation and systemic elimination which might be an explanation for the improved antitumor effect of these preparations.

Animals↗
PubMed1986

Modulation of the effects of fluoropyrimidines on toxicity and tumor inhibition in rodents by uridine and thymidine.

Uridine and/or thymidine were administered concomitantly with 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-dFUR) to mice and rats in order to establish whether the physiological nucleosides acting in vitro as antagonists can diminish fluoropyrimidine toxicity in vivo. In addition, the influence of orally co-administered uridine on antitumor activity of 5-FU and 5'-dFUR in mice has been studied. All co-administrations aggravated the general toxicity of both fluoropyrimidines. Tumor inhibition was enhanced by uridine, but the therapeutic ratio was not improved compared to monotherapy with either 5-FU or 5'-dFUR.

Animals↗
PubMed1985

5'-O-Palmitoyl- and 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine--novel lipophilic analogues of 5'-fluoro-2'-deoxyuridine: synthesis, incorporation into liposomes and preliminary biological results.

5'-O-palmitoyl- and 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine were prepared by the reaction of 5-fluoro-2'-deoxyuridine in dimethylacetamide with palmitic acid chloride. The incorporation of the synthesized prodrugs into liposomes composed of egg phosphatidylcholine/stearylamine/cholesterol/alpha-tocopherol at a molar ratio of 10:1:2:0.05 was nearly quantitative; homogeneous bilayer vesicles (75 nm diameter) were obtained. Preliminary tolerance studies revealed that the prodrug-liposome preparations are about 20-60 times more toxic than the parent drug. The prodrugs incorporated into liposomes were 10 to 30 times more active against murine colon 38 carcinoma compared to the free drug. In comparison to the administration of the prodrugs in peanut oil the liposomal preparations seem to exert improved effects and represent a valuable drug delivery system for parenteral applications.

Animals↗
PubMed1985

The effects of arotinoids on rat mammary carcinogenesis.

The influence of two retinoids, Ro 13-6298, an arotinoid ethyl ester, and Ro 15-1570, an arotinoid ethyl sulfone, on rat mammary carcinogenesis was investigated. Mammary carcinomas were induced by oral administration of 15 mg dimethylbenz(a)anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Oral administration of the two retinoids significantly inhibited the development of tumors. The number and volume of mammary neoplasms were influenced in a dose-dependent manner.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

The antitumour effect of lipophilic derivatives of 5-fluoro-2'-deoxyuridine incorporated into liposomes.

Lipophilic prodrugs of 5-fluoro-2'-deoxyuridine (FUdR), namely 5'-O-palmitoyl-5-fluoro-2'-deoxyuridine (5'-O-palm-FUdR) and 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (3',5'-O-dipalm-FUdR), were incorporated into bilayer liposomes. Prodrug incorporation into positively charged liposomes was quantitative and stable, homogeneous bilayer vesicles were obtained. The maximal amounts of prodrug incorporation are 200 micrograms for 5'-O-palm-FUdR and 90 micrograms for 3',5'-O-dipalm-FUdR per mg egg phosphatidylcholine as matrix lipid. The prodrug-liposome preparations were tested in vivo against mammary carcinoma 13/C, Lewis lung carcinoma and L1210 leukaemia and compared to the cytostatic activity of free FUdR and of the prodrugs dissolved in peanut oil. Intraperitoneally administered prodrugs either incorporated into liposomes or dissolved in peanut oil inhibited tumour growth in all animals. The comparison of the doses required for tumour growth inhibition showed that both prodrugs were active at concentrations 20-75 times lower as compared to unmodified FUdR. However, due to the increased toxicity of the prodrug-liposome preparations, the therapeutic index of the parent drug FUdR could not be improved. The cytostatic effect of the prodrug preparations may be explained by altered pharmacokinetic properties of the FUdR derivatives and the additional sustained release action the liposomes are providing. A further increase of the antitumour activity may be obtained by the attachment of tumour-specific antibodies to the surface of such prodrug-containing liposomes.

Animals↗