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Antiproliferative activities of all-trans-retinoic acid (RA, CAS 302-79-4) and some retinoid derivatives (all-trans-retinyl-beta-D-glucuronide (RYG), methyl-(1-O-retinoyl-beta-D-glucopyranoside) uronate (MRG), all-trans-retinoic acid beta-D-galactopyranosyl ester (RGA), and all-trans-retinoic acid beta-D-glucopyranosyl ester (RGU)) were determined by microculture tetrazolium assay (MTT assay) and cell counting by Coulter Counter (CC) in breast (MCF7, MDA MB 231) and colon (SW 948) cancer cell lines of human origin. RA, MRG, RGU, and RGA (5, 25 mumol/l) were significantly more growth-inhibitory in MCF7 cells, which are known to be cellular retinoic acid-binding protein (cRABP) and cellular retinol binding protein (cRBP) positive, than in MDA MB 231 cells which are cRABP and cRBP negative. RYG was active only in MDA MB 231 cells. RA, MRG, RGA and RGU (25 mumol/l) stimulated the proliferation of SW 948 cells as determined by CC, whereas the MTT assay indicated an inhibition of cell growth.

Miltefosine (hexadecylphosphocholine, HPC, CAS 58066-85-6) was investigated in transplanted primary methylnitrosourea-induced PYH mammary carcinoma of F344 rats. The therapy was performed in the 5th and 10th passage. At first HPC (113 mg/kg body weight) significantly reduced the median tumor volume, but a loss of activity was observed in the 10th passage. To explain the loss of sensitivity and to obtain information on the mechanism of action histology, cytoskeleton and hormone receptor content were investigated. The most important change was observed in the histopathology of the tumor. The initial tubular papillary adenocarcinoma was transformed into a malignant adenoacanthoma with epithelial structure. Vimentin as an endothelial marker of the cytoskeleton was equally expressed in all passages. Cytokeratin was weakly expressed in the earlier passages and intensively present in the late passages. The histopathological change from tubular adenocarcinoma to malignant adenoacanthoma might be caused by an overgrowth of the primary epithelial tumor cells or by a real transformation in the morphological characteristics of the tumor, which may occur during repeated transplantation.

Six ruthenium derivatives were evaluated in vitro in two human colon cancer cell lines (SW707 and SW948) utilizing the microculture tetrazolium test (MTT) and cell counting with a Coulter Counter. The ruthenium compound sodium-(tetrachloroimidazoledimethylsulfoxideruthenate)- bisdimethylsulfoxide (Na(RuDMSOimCl4)) showed the best efficacy in inhibiting cell proliferation of both colon cancer cell lines followed by the other DMSO ruthenium compound sodium-(tetrachloroindazoledimethylsulfoxideruthenate) - bisdimethylsulfoxide (Na(RuDMSOIndCl4)), as demonstrated by IC50 values (80 and 90 micrograms/ml in SW707 and SW948 cell lines for Na(RuDMSOImCl4); 155 and 165 micrograms/ml in SW707 and SW948 cell lines for Na(RuDMSOIndCl4), respectively). Out of the ruthenium derivatives without DMSO, transindazolium - [tetrachlorobis(1H - indazole)ruthenate (III,N2)] (HInd[RuInd2Cl4(N2)]), was as active as its DMSO-containing congener whereas trans-imidazolium- [tetrachlorobisimidazoleruthenate)(III)], (HIm(RuIm2Cl4)) was less active, as shown by the IC50 values: (HIm (RuIm2Cl4) = 250 and 260 micrograms/ml in cell lines SW707 and SW948; HInd[RuInd2Cl4(N2)] = 110 and greater than 200 micrograms/ml in cell lines SW707 and SW948, respectively). The other ruthenium derivatives containing pyrazole and triazole as ligands (trans - pyrazolium (tetrachlorobispyrazoleruthenate) (III), PzH(RuPz2Cl4) and triazolium(tetrachlorobistriazoleruthenate) (III), TrH(RuTr2Cl4)) were active only at high concentrations that cannot be regarded as realistic in vivo, as shown by the respective IC50 values: (PzH(RuPz2Cl4) = 1056 and 750 micrograms/ml in cell lines SW707 and SW948; TrH(RuTr2Cl4) = 350 and 300 micrograms/ml in cell lines SW707 and SW948). The promising activity of ruthenium compounds with DMSO, indazole and imidazole as ligands should be evaluated in vivo for elucidating their possible role in the treatment of colorectal cancer.

Cells derived from 9 human tumors were tested in vitro using 5 doses ranging from 1 to 5000 units of recombinant human erythropoietin (rhEpo) per ml to assess a proliferation response to this hormone. The following tumors were used: 2 melanomas, 1 hepatoma, 3 renal cell carcinomas, 1 adenocarcinoma of the lung, and 2 mammary carcinomas (with and without sex steroid hormone receptors). Compared to untreated cells, none of the cell lines exposed to rhEpo revealed differences in proliferation extending beyond the limits of methodological fluctuation. rhEpo thus does not have any effect on the growth of human tumors in vitro under the experimental conditions applied.

The in vitro antineoplastic activity of hexadecylphosphocholine (HPC, CAS 58066-85-6) on methylnitrosourea (MNU)-induced mammary carcinoma in Sprague-Dawley rats and human mammary carcinoma was investigated with the modified Hamburger-Salmon-Colony-Assay (HSCA). The effect of HPC was also compared with ilmofosine (alkyllysophospholipid derivative) and N-(2-chloroethyl-N-nitroso-N'-2-hydroxyethylurea (HECNU). Moreover, the modified HSCA was performed with bone marrow cells and KB cells. In this investigation, no specific antineoplastic effect of the test compounds on MNU-induced mammary carcinoma and human mammary carcinoma was found in HSCA. Thus the antineoplastic activity of the compounds could not be compared on these cell types. In vitro, effects were only observed in bone marrow and KB cells at a very low concentration. The in vitro effect of HPC on mammary carcinoma cells, evaluated through HSCA, did not predict the effect of HPC in vivo. The reason has remained unknown but some hypotheses are discussed. Because of the contrary results of HPC in vitro and in vivo, it should be pointed out that drug development in this class of compounds mainly has to depend on in vivo experiments.

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

The anticancer efficacies of three 1-(2-chloroethyl)-1-nitroso-3-(2- hydroxyethyl)urea (HECNU) derivatives--4-acetoxybisdesmethyltamoxifen-1,4-hemisuccinate-H ECNU (4-OAc-BDMT-hs-HECNU), 17-beta-estradiol-1,4-hemisuccinate-HECNU (E2-hs-HECNU) and 17-dihydrotestosterone-1,4-hemisuccinate-HECNU (DHT-hs-HECNU)--are compared with their unlinked equimolar mixtures using the estrogen and androgen receptor positive cell line MCF-7. Following 72 h incubation at a concentration of 100 mumol/l, 4-OAc-BDMT-hs-HECNU and DHT-hs-HECNU have a growth inhibitory effect of 76% and 73%, respectively, whereas E2-hs-HECNU causes an inhibition of 55%. Within this time period, DHT-hs-HECNU (100 mumol/l) is more effective as compared to the unlinked equimolar combination of HECNU plus dihydrotestosterone; E2-hs-HECNU (100 mumol/l) is slightly more and 4-OAc-BDMT-hs-HECNU (100 mumol/l) is even less effective than the respective unlinked equimolar mixtures. At this concentration (100 mumol/l) the growth inhibitory effect of 4-OAc-BDMT-hs-HECNU is not antagonized by coincubation with estradiol.

The tumor inhibitory effect of a standardized mixture of valepotriates was investigated. The growth of 3 transplanted and 2 chemically induced autochthonous rat tumors was not influenced significantly by intravenous or peroral administration of these compounds.