Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.
A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
The inhibition of estrogen is a particularly useful strategy for the treatment of hormone-dependent breast tumors in postmenopausal females and possibly in premenopausal women and as a chemosuppressive in women at high risk of developing breast cancer. Nonsteroidal antiestrogens which exhibit potent antitumor effects represent a major advance in the management of breast cancer. Considerable effort by many research groups has been devoted to the search for novel pure nonsteroidal antiestrogens with the hope of finding antitumor agents that would be useful in estrogen receptor (ER) positive or estrogen receptor (ER) negative disease. The reasoning behind the search for pure antiestrogens is based on the recognition that antiestrogens generally possess the partial estrogenic activity and a complete blockade of estrogen action cannot be achieved by agents like tamoxifen. Novel pure antiestrogens should be more effective than partial agonist in reducing the mitogenic action of estrogen on the growth of breast tumors and complete ablation of hormonal-dependent tumor growth is very desirable since it could provide a more rapid and longer-lasting remission. In addition, pure antiestrogens could be more effective in patients who experience a relapse during tamoxifen therapy, serving as a second-line treatment, and have the potential of demonstrating greater efficacy in first-line treatment of advanced breast cancer. This review covers the chemistry of the experimental and potentially useful nonsteroidal antiestrogens and the only agent, tamoxifen, used in the therapy of breast cancer with special emphasis on structure-activity relationships. Special attention was paid to the structural classes [1,2-bis(hydroxyphenyl)ethane; 2-phenylindoles; indolo[2,1-a] isoquinolines; 2-phenylbenzo[b] thiophenes; dibenzo[a,g]quinolizinones; triarylpropenones (TAPs); 3,4-dihydro-1-naphthalenyl methanones; 3-aroyl-2-arylbenzo[b]thiophenes; 2,3-diaryi-2H-1-benzopyrans; triphenyl ethylenes (TPEs); dichlorodiarylcyclopropanes (DDACs) and the 1,1-dichloro-2,2,3-triarylcyclo propanes (DTACs)] whose agents demonstrated particular activity in the in vitro receptor binding affinity assay and the in vivo uterotrophic and antiuterotrophic assays. Where possible, the in vitro antiproliferative properties of these agents in cell culture assays also were discussed.
Vaccination using dendritic/tumor cell hybrids represents a novel and promising cancer immunotherapy. We have developed a technology that can instantly purify the hybrids (dendritomas) from the fusion mixture of dendritic cells (DCs) and tumor cells. Our animal studies and a phase I study of stage IV melanoma patients demonstrated that dendritoma vaccination could be conducted without major toxicity and induced tumor cell-specific immunological and clinical responses. In this pilot study, ten stage IV renal cell carcinoma patients were studied. Dendritomas were made from autologous DCs and tumor cells and administered by subcutaneous injection. After initial vaccination, three escalating doses of IL-2 (3, 6, and 9 million units each) were followed within five days. This treatment regimen was tolerated well without severe adverse events directly related to the dendritoma vaccine. Most adverse events were related to IL-2 administration or pre-existing disease. Patient-specific immune responses were evaluated by flow cytometric measurement of interferon-γ-producing T-cells before and after vaccination in response to stimulation with tumor antigens. Nine out of nine patients eligible for the analysis showed an increase of IFN-γ-expressing CD4 + T cells after vaccination(s); while five out of eight patients eligible for the analysis showed an increase of IFN-γ-expressing CD8 + T cells. Clinical responses were documented in 40% of the patients, three with stabilization of disease and one with a partial response documented by a reduction in tumor size. This pilot study demonstrated that dendritoma vaccines could be administered safely to patients with metastatic renal cell carcinoma, while producing both clinical and immunologic evidence of response.
The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine). Structural modification of 1-(alkylamido)-, -(alkylthio)-, and -(alkyloxy)propyl backbones has provided further insight into the structure-activity relationships of these lipids. In this study, a long saturated C-1 chain and a three-carbon backbone with a single short C-2 substituent were preferred. At the positively charged nitrogen of phosphocholines, fewer than three substituents caused a significant loss of activity, and substituents larger than methyl decreased activity slightly. In the nonphosphorus compounds, many nitrogen heterocycles and also a sulfonium moiety were incorporated without changing the degree of activity; however, a thiazolium group decreased activity. The most active compound, 29 [N-[3-(hexadecyloxy)-2-methoxypropyl]-3-(hydroxymethyl)pyridinium bromide], was approximately twice as active as the reference standard, ET-18-OMe, in a trypan blue dye exclusion assay.
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