n-solanesyl-n-n--bis(3-4-dimethoxybenzyl)ethylenediamine and Carcinoma--Squamous-Cell

Combined effect of bleomycin (BLM) and N-solanyl-N, N'-bis (3, 4-di-methoxy-benzyl)-ethylenediamine (SDB-ethylenediamine), a synthetic isoprenoid was studied on 3 oral squamous carcinoma cell lines (SCCTF, SCCKN, SCCRY) and clonal cell lines from SCCRY in vitro and on transplantable nude mouse tumors. The cytotoxicity of SDB-ethylenediamine varied among those cell lines in vitro. SDB-ethylenediamine potentiated more than 2-fold the cytotoxic effect of BLM in 6 cell lines, but no distinct correlation was found between cytotoxicity of SDB-ethylenediamine and potentiation by BLM. Compared with verapamil, the cytotoxic effect of BLM was potentiated 3.9-fold by SDB-ethylenediamine in SCCTF. The growth of the transplantable nude mouse tumors (SCCRY and SCCTF) was strongly suppressed when BLM was combined with SDB-ethylenediamine. Correlation between BLM resistance and potentiation of BLM by SDB-ethylenediamine was not observed in this experiment.

Topics: Animals; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Drug Resistance; Drug Synergism; Ethylenediamines; Humans; Male; Mice; Mice, Nude; Mouth Neoplasms; Neoplasm Transplantation; Terpenes; Tumor Cells, Cultured

A newly synthesized isoprenoid, N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine, has a verapamil-like structure but no calcium channel blocking activity. The isoprenoid enhanced the cytotoxic effect of a conjugate of epidermal growth factor coupled with Pseudomonas exotoxin in human KB cells. By using iodinated epidermal growth factor ([125I]EGF), the effect of the isoprenoid on intracellular transport of EGF was examined. The isoprenoid did not affect the binding and uptake of [125I]EGF by KB cells. The release of radioactivity associated with [125I]EGF into medium was slow in the presence of the isoprenoid. Density gradient fractionation studies using cell homogenates suggest that [125I]EGF accumulates in an undegraded form in lysosomes when cells are treated with the isoprenoid. The pH value in lysosomes of KB cells was 5.5, and SDB did not affect significantly the pH value at the concentrations used to potentiate the cytotoxicity of chimeric toxins. Electron microscopy showed an increased number of electron-dense bodies in KB cells grown for 24 hr with 17-51 micrograms/ml isoprenoid. The potentiating action of chimeric toxins by the isoprenoid is discussed in relation to the altered lysosomal function in treated cells.

Topics: ADP Ribose Transferases; Bacterial Toxins; Carcinoma, Squamous Cell; Cell Line; Drug Resistance; Drug Synergism; Epidermal Growth Factor; Ethylenediamines; Exotoxins; Humans; Kinetics; Lysosomes; Microscopy, Electron; Pseudomonas aeruginosa Exotoxin A; Terpenes; Virulence Factors

A colchicine resistant clone, Chr-24, derived from the human carcinoma KB cell line is extensively resistant to multiple drugs including vinblastine, vincristine, Adriamycin, actinomycin D, and daunomycin. In comparison with KB cells, very low accumulation of daunomycin or vincristine is observed in multidrug-resistant cells. Two isoprenoids with 9 to 10 isoprene chains (polyprenoids), N-(p-methylbenzyl)decaprenylamine and N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine overcame the multidrug resistance almost completely in cultured Chr-24, whereas they only slightly sensitized the parental KB cells to anticancer agents. Both isoprenoids enhance the accumulation of vincristine or daunomycin in Chr-24, possibly by inhibiting efflux and also by enhancing influx of anticancer agents. A verapamil-like structure of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine is discussed in relation to its ability to overcome drug resistance.

Topics: Antineoplastic Agents; Biological Transport; Carcinoma, Squamous Cell; Cell Cycle; Drug Resistance; Ethylenediamines; Humans; KB Cells; Kinetics; Terpenes