Therapeutic response to taxol of six human tumors xenografted into nude mice.

To test the antineoplastic activity of taxol, a natural product isolated from yew (Taxus baccata L.), six human tumors transplanted into athymic mice were used (primary tumors of breast, endometrium, ovary, brain, lung and a recurrence of tongue tumor). While the growth rates varied with the histopathological characteristics of different tumor types, all mice were treated at a mean tumor volume of 200 +/- 8 mm3. Taxol was given SC at a dose level of 12.5 mg/kg per injection per day for 5 consecutive days out of 7 over a period of 3 weeks. With this schedule antitumor responses were obtained in all of the six neoplasms xenografted into nude mice. In the case of the ductal carcinoma of the breast total tumor regressions were observed in four of the five treated animals. In the five other experimental models taxol produced significant growth delays. We believe that the results of these initial tests on the nude mouse--human tumor xenograft system are convincing and justify clinical assessment of this drug.

Antineoplastic activity of two taxol derivatives on an ovarian tumor xenografted into nude mice.

In order to compare the antineoplastic activities of taxol A, taxol B, a mixture of the two (taxol A 72%) and vinblastine, a human ovarian tumor serially transplanted into 104 female athymic mice was used. In the first experiment (11th passage), the antineoplastic activities of taxol A, taxol B and the mixture taxol AB were tested. The same dose was used in each case (12.5 mg/kg i.e. 1/20 of the evaluated LD50 value). It was administered subcutaneously for 5 consecutive days. Three courses of treatment were performed, with 2 rest periods of 1 week in between. All the taxol derivatives produced a statistically significant delay in the tumor growth. However, taxol B had the lowest chemotherapeutic response. In the second experiment (18th passage), different dose levels were administered (mixture 12.5 mg/kg/day x 4 - taxol A 8.8. mg/kg/day x 4 - taxol B 3.5 mg/kg/day x 4 - vinblastine 0.5 mg/kg/day x 2). For all the taxol derivatives 4 treatment courses with 3 rest periods of 4 days were used, and for vinblastine 4 treatment courses with 3 rest periods of 1 week. At the end of the second experiment, vinblastine, taxol A and a mixture of the two showed similar significant activity, whereas no objective antitumor response was observed following the taxol B treatment at the dose level chosen. The experimental results obtained clearly demonstrate that, in the taxane system, the greatest degree of antineoplastic activity can be attributed to taxol A.

Isoenzyme pattern of enolase in human lung tumor xenografts in nude mice.

A simple method is described which allows easy determination of neuroendocrine (NE) differentiation in human broncho-pulmonary tumor models grown in heterotransplanted nude mice. Enolase (EC 4.2.1.11) isoenzyme composition is studied using the electrophoretic method in xenograft tumor homogenates. The relatively large amount of alpha gamma and gamma gamma isoenzymes (neuron-specific enolase (NSE] is indicative of the neuroendocrine differentiation level of these tumors. The gamma gamma isoenzyme is present at a high level (M +/- SE: 10 +/- 2%) in all NE tumor models and absent in non NE tumor models. The alpha gamma isoenzyme is found in a significantly higher proportion in NE tumor models (30 +/- 2%) than in non NE tumor models (9 +/- 2%) (p less than 0.001). Moreover it is possible to discriminate between human and mice isoenzymes to estimate the proportion of mouse tissue hat is present in the xenograft.

Antibacterial, antifungal and antitumoral activities of 5-carbamoyloxy and 5-acyloxynaphthalene-1,8-carbolactones.

Naphthalene-1,8 carbolactone derivatives have been investigated in order to compare their activities using antitumoral, antibacterial and antifungal tests in vitro. The effect of 5-substitution is the reduction of the toxicity and the suppression of the antibiotic activity. The best results were obtained with the ester series (5-acetoxy and 5-propionyloxy) on both antitumoral and antifungal tests.

Antitumor activity of patulin and structural analogs.

A comparison between the cytotoxicity and the antitumor activity of patulin and five structural analogs (isopatulin, dehydroisopatulin, dimethylisopatulin, trimethylisopatulin and isopropylisopatulin) has been established. In vitro assays using L 1210 and P 388 cells showed that the structure of the pyranic ring as well as the nature of the substituents influenced the observed activities. Among the five structural analogs of patulin assayed in vivo against Ehrlich carcinoma, L 1210 and P 388 leukemias, dehydroisopatulin was the only one to be active on all 3 types of tumors at a dose of 100 mg.kg-1.d-1. The ratio between the LD50 in mice and the active dose was 5 while with patulin it was 10. It can be assumed that the lactone function is not solely responsible for the activity of patulin and its structural analogs.

[Influence of retinoids on the bioavailability of methoxy-8-psoralen]. / Influence des rétinoïdes sur la biodisponibilité du méthoxy-8-psoralène.

The retinoid-PUVA combination has been recognized as a satisfactory treatment of psoriasis. The absorption of 8-methoxypsoralen (8-MOP) is subject to wide interindividual variations under the influence of factors that are not yet known with certainty but are independent of age, sex and food taken at the same time as the psoralen. Whether concomitant retinoid administration influences the bioavailability of 8-MOP was considered an interesting question. The pharmacokinetics of 8-MOP were studied and compared in two populations of psoriatic patients: 119 patients treated with PUVA alone (psoralen-ultraviolet A) and 40 patients treated with the etretinate-PUVA combination (RePUVA). 8-MOP was assayed by the modified Ljunggren method 1 h, 1 h 30, 2 h, 2 h 30, 3 h and 4 h after ingestion of 8-MOP. The pharmacokinetic values recorded were: time and peak value of maximum plasma 8-MOP concentration (Tmax, Cmax) and area under the curve of time-related 8-MOP concentrations (AUC). The results obtained were as follows: Tmax PUVA 2 h 02 +/- 53 min RePUVA 1 h 56 +/- 50 min Cmax PUVA 159.12 +/- 88.85 ng/ml RePUVA 163.63 +/- 92.85 ng/ml AUC PUVA 343.33 +/- 211.06 ng*h/ml RePUVA 388.12 +/- 251.03 ng*h/ml Statistical analysis showed no significant difference in pharmacokinetic values between patients on PUVA alone and patients on RePUVA. Taking etretinate therefore does not alter the pharmacokinetics of 8-MOP and should not require any change in PUVA treatment.

Analysis of Usnea fasciata crude extracts with antineoplastic activity.

Different fractions, isolated from the lichen Usnea fasciata, were analyzed by PC, TLC, and RP-HPLC. Analysis of the organic phases, mainly containing phenolics, revealed that usnic acid is the main product from secondary metabolites, whereas the polysaccharides isolichenin and raffinose are the most abundant water-soluble carbohydrates. Fractions containing usnic acid, as well as those containing isolichenin, showed moderate activity against sarcoma 180 and Ehrlich tumor cells. High antitumoral activity, near 90% inhibition, was found associated with the fraction containing raffinose.

Influence of the diet on the plasma kinetics of 8-methoxypsoralen.

The plasma kinetics of 8-methoxypsoralen (8-MOP) have been determined in 103 patients treated by PUVA in the routine conditions in which PUVA therapy is carried out in hospital. 8-MOP is taken with breakfast; four types of breakfast were available, which differed by their lipid content; this study showed that the diet has no influence on the bioavailability of 8-MOP.

[Annomonysvin: a new cytotoxic gamma-lactone-monotetrahydrofuranyl acetogenin from Annona montana]. / Annomontacine: une nouvelle acétogénine gamma-lactone-monotetrahydrofurannique cytotoxique de l'Annona montana.

The structure of annomontacin [I], a novel monotetrayhydrofuran fatty acid gamma-lactone (acetogenin) isolated from the seeds of Amnona montana, was determined by spectral analysis. The cytotoxicities in vitro of annomontacin [I], annonacinone [2], and annonacin were measured against murine leukemia L1210, human breast adenocarcinoma MDA-MB231, and human breast carcinoma MCF7 cell lines and compared with adriamycin.

Diels-Alder reactions between dienamides and quinones: stereochemistry of the cycloadditions and cytotoxic activity of the adducts.

Tetrahydronaphthoquinones and tetrahydroanthraquinones bearing an amido group have been prepared by Diels-Alder reactions between (E)-1-(N-carbobenzyloxyamino)-1,3-butadiene (2) or (E)-1-(N-benzoyl-N-benzylamino)-1,3-butadiene (5) and benzoquinone or 5-substituted naphthoquinones. The stereochemistry of the cycloadditions was investigated. A high regioselectivity was observed in the reaction of the diene carbamate 2 with 5-methoxy and 5-acetoxy naphthoquinones. This latter gave the unexpected 1,8-regioisomer 3d. The cycloadditions of the dienamide 5 with naphthoquinones 1 (R = OH, OMe, OAc) are regiospecific. Assignment of the structure of the tetrahydroanthraquinone 6b is in good agreement with the known directing effect of the 5-hydroxy group of juglone 1b in analogous Diels-Alder reactions. With 5-methoxy and 5-acetoxy naphthoquinones, the opposite regiochemistry observed is consistent with the electron-donating influence of the methoxy or acetoxy group, making the C-3 carbon atom more electron deficient. Aromatization of the adducts 6b and 7c was accompanied by an unusual elimination of the amido moiety. Thus, 1-hydroxy and 1-methoxy anthraquinones were obtained. Reactions of the dienes 2 and 5 with benzoquinone gave the tetrahydronaphthoquinones 9 and 10 with an endo stereospecificity. Oxidation of 9 by activated manganese dioxide gave the naphthoquinone 11. These compounds were submitted to in vitro cytotoxic assays towards murine L 1210 leukemia cells and clonogenic human tumor cell line MDA-MB 231. The naphthoquinone derivatives 9, 10 and 11 had significant activities with IC50 less than or equal to 0.4 microgram/ml towards these two tumor cell systems.

Determination of 8-methoxypsoralen kinetics: a relevant factor in the treatment of psoriasis by psoralen plus ultraviolet A therapy.

We compared the efficacy of psoralen plus ultraviolet A (UVA) therapy in 2 groups of psoriatic patients: a group of patients treated by a protocol adapted to the results of 8-methoxypsoralen (8-MOP) plasma kinetics (kinetics group) versus a control group of patients treated according to Pathak's standard protocol (UVA exposure 2 h after oral administration of a dose of 8-MOP equal to 0.6 mg/kg) (control group). The 8-MOP plasma kinetics were determined before the beginning of treatment. The parameter for comparison is the rapidity of clearing, taking into account the number of UVA exposures and UVA joules received. The analysis of the results observed show a 26.6% decrease in the number of UVA exposures and a 38.4% decrease in the dose of UVA received. These results are confirmed by the individual analysis of the rapidity with which the clearance of psoriatic lesions was obtained in patients who were treated with the standard PUVA protocol during the first attack and with the adapted protocol during the second attack.

Antibacterial, antifungal and antitumoral activities of Micromycetes. I. Preliminary study.

The ability of 211 strains of Micromycetes to produce antibiotic, antifungal and antitumoral compounds has been investigated in vitro using test strains and P 388 leukemia cells. Cytotoxicity was determined on Vero cells. Convenient activities were obtained depending on the taxonomic group. Finally, 17 strains of Micromycetes were selected for their antibacterial or antifungal activities and 12 for their antitumoral properties. Investigations are in progress concerning these activities.

Derivatives of methyl vinyl sulfone. Distribution and elimination of methyl (2,2-diphenyl)-vinyl sulfone labelled with 14carbon in mice.

The investigation of methyl (2,2-diphenyl)-vinyl sulfone (14C-MDVS) administered i.p. in mice shows that this product appears rapidly in the general circularoty system. The blood concentration of MDVS reaches a maximum 1 h after injection. Part of the MDVS is bound to the plasma proteins. Infrared spectrometry analysis of radioactive products eliminated by the urine confirms that the product is not split, but also reveals the presence of hydroxyl and carbonyl groups in the metabolic conversion products.

[Tamoxifen fluorescence as a marker of hormone-dependence: physicochemical aspects]. / La fluorescence du tamoxifène comme marqueur de l'hormonodépendance: aspect physico-chimique.

In acid solutions, Tamoxifen is protonized and forms with eosin a fluorescent ionic association (lambda exc 480 nm, lambda em 565 nm). This reaction is quantitatively linked to the concentration of Tamoxifen. Thus the Tamoxifen induced fluorescence observed in hormone-dependent malignant breast tumor cells after Papanicolaou staining procedure, appears as a consequence of the binding of Tamoxifen to eosin.

Studies of antitumor activity of the culture filtrate of Hohenbuehelia geogenius (D.C. ex Fr.) Sing (basidiomycete).

The antitumor activity of the culture filtrate of the fungus Hohenbuehelia geogenius (basidiomycete) was investigated on two rapidly growing grafted tumors: Ehrlich's ascites carcinoma and L1210 lymphoid leukemia and also on a slow growing spontaneous mammary tumor in PS strain mice. The mycelial culture filtrate inhibited the growth of these three tumors. An active substance was isolated from the mycelial culture filtrate by solid-liquid extraction and column chromatography. Its chemical structure was elucidated with ultraviolet and infrared spectra, mass spectrum, nuclear magnetic resonance, and X-ray diffraction.

[Action of taxol on human tumors transplanted in athymic mice]. / Action du taxol vis-à-vis de tumeurs humaines transplantées sur des Souris athymiques.

In order to study the antitumour activity of taxol (a diterpene of the taxane type) isolated from Yew: Taxus baccata L. (Taxacae), human tumours implanted as xenografts in athymic Mice were used. Swiss nude mice were treated subcutaneously (12.5 mg/kg/injection/day for 5 consecutive days out of 7, over a period of 3 weeks). Treatment by taxol of a liver metastasis of a breast tumour, a tongue primary tumour and a skin metastasis of bronchial carcinoma gave statistically significant results (0,01 greater than P greater than 0,001 and P less than 0,001). However, taxol showed a very moderate antitumour activity against a transplanted primary tumour of the colon.