naphthoquinones and Laryngeal-Neoplasms

Glycoside derivatives of diospyrin (1) were synthesized for the first time, and the cytotoxicity of the novel compounds vis-à-vis their precursors were evaluated against two human cancer cell lines, viz. malignant melanoma (A375) and laryngeal carcinoma (Hep2). The IC(50) values were in the low micromolar range for all the compounds tested, and A375 cells showed comparatively greater sensitivity than Hep2. Most of the compounds exhibited enhanced activity as compared to the plant-derived quinonoid precursor of the series (1), while the aminophenyl mannosyl (6) was found to be the most effective derivative. In A375 cells, 6 (IC(50) = 0.02 microM) showed the maximum increase in cytotoxicity (approximately 35-fold) over that of 1 (IC(50) = 0.82 microM). Again, when the glycosides were evaluated at a given concentration (0.1 microM) for their relative capacity to generate ROS from A375 cells, the compound 6 could produce the highest amount of ROS. Incidentally, this derivative also showed a comparatively lower toxicity (IC(50) approximately 41 microM) when tested against normal human peripheral blood mononuclear cells, indicating a fair prospect of its development as a novel chemotherapeutic agent for the treatment of malignant melanoma.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Glycoconjugates; Humans; Laryngeal Neoplasms; Melanoma; Naphthoquinones; Reactive Oxygen Species

3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (beta-lapachone) is a novel DNA repair inhibitor. It was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers. Logarithmic-phase growing human epidermoid laryngeal carcinoma (HEp-2) cells were allowed to incorporate pyrimidine analogues for 48 h (approximately two cell doublings) and then were X-irradiated and subjected to various posttreatments. beta-Lapachone synergistically increased the dose enhancement ratios (DERs) of all analogues screened, with the exception of the 2'-chloro derivative of 5-bromodeoxyuridine. For example, following 5-bromodeoxycytidine sensitization an X-ray DER value of 1.87 +/- 0.04 at 1% survival was increased to 3.51 +/- 0.42 due to a 4-h post-X-irradiation exposure to 4 microM beta-lapachone. Do and Dq values for halogenated pyrimidine-sensitized human epidermoid laryngeal carcinoma cells were decreased 1.4- to 5.4-fold and 1.4- to 4.0-fold, respectively. beta-Lapachone had little effect upon the cytotoxicities of unirradiated human epidermoid laryngeal carcinoma cells whether or not they were previously exposed to any of the halogenated pyrimidine radiosensitizers. beta-Lapachone treatment following X-irradiation of cells that had not incorporated a pyrimidine analogue exhibited DER values of 1.38 +/- 0.05 and 1.40 +/- 0.01 at 10 and 1% survival levels, respectively. beta-Lapachone enhanced the radiosensitization of deoxycytidine analogues to a greater extent than the structurally related deoxyuridine analogues. Greater DERs and lower Do and Dq values were found for deoxycytidine than for deoxyuridine analogue radiosensitizers following beta-lapachone treatment. This agent may improve presently used radiation therapies and enhance proposed strategies which utilize deoxycytidine analogue radiosensitization together with protection of normal tissues by tetrahydrouridine to achieve tumor-selective radiotherapy.

Topics: Bromodeoxycytidine; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cell Line; Cells, Cultured; DNA Repair; Drug Synergism; Humans; Laryngeal Neoplasms; Naphthoquinones; Radiation-Sensitizing Agents

Topics: Amnion; Animals; Carcinoma; Cattle; Cell Line; Culture Techniques; Fibroblasts; Haplorhini; HeLa Cells; Humans; Kidney; Laryngeal Neoplasms; Lung; Naphthoquinones; Tritium