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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the modification of camptothecin (CPT)-induced cell killing by hyperthermia in a radioresistant human melanoma (Sk-Mel-3) and a human normal (AG1522) cell line. CPT, a topoisomerase (topo) I inhibitor, was given as a 1 h exposure at variable doses up to 34 microM; hyperthermia was given either before or following CPT treatment. Hyperthermia was given either as a treatment of 41 degrees C for 8 h (termed lower temperature hyperthermia, LTH) or 45 degrees C for 15 min (termed higher temperature hyperthermia, HTH). LTH preceding CPT treatment had no effect on Sk-Mel-3 but potentiated killing of AG1522 cells. HTH preceding CPT treatment, however, almost completely abrogated the toxicity of CPT to both Sk-Mel-3 and AG1522 cells. These results therefore provided evidence for a lack of enhancement of CPT toxicity towards Sk-Mel-3 cells when hyperthermia preceded treatment with CPT. There was also no potentiation of killing of both cell lines when LTH followed treatment with CPT. In contrast, the killing of Sk-Mel-3 cells was slightly potentiated, whereas that of AG1522 cells was reduced, when HTH followed CPT. These results therefore suggested a potential for enhancement of killing of Sk-Mel-3 relative to AG1522 cells when HTH, but not LTH, followed CPT treatment. In addition, we found that a preceding exposure ot HTH did not affect either accumulation or efflux of[3H]CPT in both cell lines. Thus the significantly reduced cytotoxicity observed under those conditions was not related simply to a modification of accumulation or efflux of CPT. We found no significant differences in the atalytic activities of topo I extracted from the nuclei of Sk-Mel-3 and AG1522 cells that were either heated under HTH conditions or that were no subjected to such treatment. These results therefore suggested that the substantial reduction of cytotoxicity seen when HTH preceded CPT treatment was also not due to an effect on topo I catalytic activity. Our results therefore demonstrate that the sequence of application of hyperthermia and CPT is very important in determining the amount and, possibly, selective potentiation of tumour relative to normal cell cytotoxicity.
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PMID:Sequence of treatment is important in the modification of camptothecin induced cell killing by hyperthermia. 888 92

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
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PMID:Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. 889 41

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.
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PMID:Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. 934 21

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. In order to establish a reproducable model system for studying the exact mechanisms conferring chemoresistance, we selected drug-resistant sublines in vitro derived from one parental human melanoma (MeWo) cell line. Four commonly used chemotherapeutic drugs (vindesine, etoposide, fotemustine, cisplatin) with different modes of action were choosen and stable sublines exhibiting four different levels of resistance against each drug were selected by continuous exposure over two years. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-resistance pattern revealed an up to 26-fold increased relative resistance against the alkylating agent fotemustine (MeWoFOTE) and an up to 35.7-fold increased relative resistance against topoisomerase-II-inhibiting etoposide (MeWoETO). Cisplatin selection (MeWoCIS) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas vindesine exposure (MeWoVIND) increased relative resistance up to 10.2-fold. Sublines selected separately for resistance to the DNA-damaging agents fotemustine, cisplatin and etoposide demonstrated strong cross-resistance. In comparison to the parental cell line drug-resistant sublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposide and fotemustine. Expression of bcl-2 family members (bax, bcl-x) was modulated by fotemustine, etoposide and cisplatin. In addition the expression of members of the fos (c-fos) and jun (c-jun, jun-D) gene family encoding transcription factors of the AP-1 complex was altered in all drug-resistant sublines. The pattern of expression varied with the inducing stimulus and this was paralleled by changes in the transactivation potential of AP-1. Our results reinforce the central role of AP-l in drug resistance probably through its participation in a programmed cellular stress response.
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PMID:Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression. 949 34

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including antibacterial, antiviral, and antimalarial properties. To date, the molecular basis for its diverse biological effects remains largely uncertain. Several lines of evidence strongly suggest that DNA might correspond to its principal cellular target. Consequently, we studied the strength and mode of binding to DNA of cryptolepine by means of absorption, fluorescence, circular, and linear dichroism, as well as by a relaxation assay using DNA topoisomerases. The results of various optical and gel electrophoresis techniques converge to reveal that the alkaloid binds tightly to DNA and behaves as a typical intercalating agent. In DNAase I footprinting experiments it was found that the drug interacts preferentially with GC-rich sequences and discriminates against homo-oligomeric runs of A and T. This study has also led to the discovery that cryptolepine is a potent topoisomerase II inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA covalent complexes and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. Taking advantage of the fluorescence of the indoloquinoline chromophore, fluorescence microscopy was used to map cellular uptake of the drug. Cryptolepine easily crosses the cell membranes and accumulates selectively into the nuclei rather than in the cytoplasm of B16 melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is also shown that the alkaloid is more potent at inhibiting DNA synthesis rather than RNA and protein synthesis. Altogether, the results provide direct evidence that DNA is the primary target of cryptolepine and suggest that this alkaloid is a valid candidate for the development of tumor active compounds.
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PMID:The DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibits primarily DNA synthesis in B16 melanoma cells. 954 44

Laser photochemotherapy of malignancies may become an effective palliative treatment for advanced had and neck cancer using light-sensitive, chemotherapeutic drugs activated in tumors via interstitial laser fiberoptics. Previously, it was reported that cultured human P3 squamous cells incubated 2 hours with daunomycin (Dn) exhibited tenfold enhanced cytotoxicity after exposure to argon laser light at 514 nm. This short-term uptake leads to drug localization in cytoplasmic and membrane sites prior to nuclear accumulation and daunomycin topoisomerase inhibition. In the current study phototoxicity of Dn-sensitized human cancer cells was tested using broad-spectrum white light compared to monochromatic green-wavelength light. Drug uptake and laser energy levels were optimized for maximum synergy. To test light-enhanced chemotherapy in vitro, the kinetics of cell uptake and toxicity of daunomycin was measured at 1, 2, and 5 microg/ml in three human tumor cell lines: P3 squamous-cell carcinoma, M26 melanoma, and TE671 fibrosarcoma. After 2 hr Dn uptake, all cell lines were tested for phototherapy response by exposure to 300- to 900-nm visible light from a xenon lamp or monochromatic 532-nm green light from a KTP laser. When the KTP laser output was varied from 0 to 120 Joules in Dn-sensitized tumor cells, a linear phototherapy response was seen with energy as low as 12 J inducing drug phototoxicity. These results provide evidence that daunomycin cytotoxicity is enhanced when exposed to 532-nm laser illumination in the three tumor types tested and confirm that the response is related to both energy level and drug dose.
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PMID:Improved photochemotherapy of malignant cells with daunomycin and the KTP laser. 969 48

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
Melanoma Res 1999 Feb
PMID:The chemoresistance of human malignant melanoma: an update. 1033 34

Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these alkaloids have been used in African folk medicine in the form of plant extracts for the treatment of multiple diseases, in particular as antimalarial drugs. To date, the molecular basis for their diverse biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with DNA and their effects on topoisomerase II. The strength and mode of binding to DNA of the three alkaloids were investigated by spectroscopy. The alkaloids bind tightly to DNA and behave as typical intercalating agents. All three compounds stabilize the topoisomerase II-DNA covalent complex and stimulate the cutting of DNA by topoisomerase II. The poisoning effect is more pronounced with cryptolepine than with matadine and serpentine, but none of the drugs exhibit a preference for cutting at a specific base. Cryptolepine which binds 10-fold more tightly to DNA than the two related alkaloids proves to be much more cytotoxic toward B16 melanoma cells than matadine and serpentine. The cellular consequences of the inhibition of topoisomerase II by cryptolepine were investigated using the HL60 leukemia cell line. The flow cytometry analysis shows that the drug alters the cell cycle distribution, but no sign of drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of DNA in cells. Cryptolepine-treated cells probably die via necrosis rather than via apoptosis. The results provide evidence that DNA and topoisomerase II are the primary targets of cryptolepine, matadine, and serpentine.
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PMID:Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine. 1038 11

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.
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PMID:Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles. 1039 85

In spite of extensive investigation, the mechanism for cell cytotoxicity of the anthracycline antitumor drug adriamycin (ADR) has not yet been completely understood but the nature of the cytotoxic effects of this drug is generally related to its interaction with nuclear components, such as DNA and topoisomerase II. In a previous paper, we studied, using Confocal Laser Scanning Microscopy (CLSM), the localization of ADR and its glutathione (GSH)-conjugate (ADRIGLU), obtained by the anaerobic reaction of the parent anthracycline with reduced GSH, in drug-sensitive and in multidrug resistant (MDR) cells. In all drug-sensitive lines used, ADR was mostly located in the nuclei, while its GSH-conjugate was found only in the cytoplasm, predominantly in the Golgi region. In this study we examined the morphological changes induced by ADR or its GSH-conjugated adduct (ADRIGLU) treatments in TVM-A12 (clone 2) melanoma and K562 erythroleukemia human cell lines, correlated to programmed cell death (apoptosis). We observed that ADR-induced apoptosis in both cell lines tested after 5 h treatment: CLSM and Scanning Electron Microscopy (SEM) showed cell shrinkage, fragmentation and condensation of nuclear chromatin, cell surface blebbing and cytoplasmic vacuolization. On the contrary, ADRIGLU-induced fragmentation and condensation of nuclear chromatin, typical of apoptosis, only after 48-72 h treatment. Cytoflourimetric assay by propidium iodide staining confirmed the data obtained by CLSM and SEM. Our data suggest that apoptosis activation by anthracycline antitumor drugs is induced not only by direct interaction with nuclear components but also with cytoplasmic compartments.
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PMID:Induction of apoptosis in neoplastic cells by anthracycline antitumor drugs: nuclear and cytoplasmic triggering? 1047 Jan 35


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