Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A theoretical study is presented for the binding of RR, SS, SR, and RS isomers 1,2-diaminocyclohexane (DAC) or cis-PtII(DAC) to DNA. cis-PtII(DAC) is ligated to N7(G) on two adjacent intrastrand guanine bases in a kinked pentamer duplex of DNA (AT, CG*, CG*, GC, AT). The relative stability of the complexes is determined by calculating the relative conformational energy of the cis-PtII(DAC)(DNA) complexes with molecular mechanics (MM) and the intrinsic binding or ligation energy with quantum mechanics (QM). The results suggest that the RR and SS isomers of PtII(DAC) adducts with DNA are more stable than the SR/RS isomer by 1.7 kcal/mol relative to the cis-PtII(DAC(H2O)2 aquated species. Calculations on the overall stability of these isomers show that the SS and RR isomers are 6.5-8.2 kcal/mol more stable than the SR/RS isomers when bound to DNA, and this is attributed to differences in the strain energy in the DAC rings. The theoretical analyses of these compounds correlate a small differential activity with the trend in intrinsic binding energies. The RR isomer is more active in B16 melanoma cells, and the SS is most active in L1210 leukemia, and in general the RR and SS isomers are more active than the SR and RS in most cell types. The fact that the activity is DNA dependent suggests that excision or repair mechanisms may be taking place and that additional mechanistic steps beyond molecular modeling and quantum mechanical calculations are required to fully understand the activity. These studies of molecular fit of cis-PtII(DAC) to DNA are used to suggest substituted DAC compounds that may yield similar binding characteristics. Modifications to yield DAC derivatives are recommended in anticipation that they may also exhibit activity.
 ...
PMID:Binding of cis(1,2-diaminocyclohexane)platinum(II) and its derivatives to duplex DNA. 230 36

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4' of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30. 238 14

Clinical trials of bleomycetin and platidiam combination were carried out in 13 patients with disseminated melanoma of the skin. Two regimens of the treatment were used. Regimen I included intravenous administration of platidiam in a dose of 20 mg/m2 with a water load on days 2, 3, 4, 5 and 6 of the treatment course and intravenous administration of bleomycetin in a dose of 30 mg/m2 on days 1 and 7. The intervals between the courses consisted of 4 weeks. Regimen II included the use of platidiam in a dose of 20 mg/m2 administered as 6-hour intravenous infusions in 1.2 1 of isotonic sodium chloride solution daily for 5 days. On the first day of this cycle bleomycetin was administered intravenously in a dose of 30 mg/m2. The cycles were performed during the 1st and the 3rd weeks of the treatment course. During the 2nd and the 4th weeks platidiam was administered in a dose of 40 mg/m2 once a week and bleomycetin was administered intramuscularly in a dose of 6 mg/m2 daily for 5 days. A more than 50 per cent decrease in the tumor formation was observed in 38 per cent of the patients. The combination had no toxic effect on hemopoiesis and may be used in new programs on chemotherapy of disseminated melanoma of the skin.
 ...
PMID:[Combination of platidiam and bleomycetin in disseminated skin melanoma]. 241 76

A novel antitumor antibiotic, 2a,3,4,5,6,6a,7,11b-octahydro-11-methoxy-12-methyl-3,6-imino-1H-2-oxa-11 c- azanaphth(1,2,3-cd)azulene-5-carboxylic acid monocitrate (quinocarmycin citrate; KW2152) was selected for investigation in a number of experimental tumor systems because of its efficacy against P388 leukemia. In the initial studies with P388 leukemia (i.p.-i.p.), KW2152 gave an increase in life span of greater than 80%. The activity was schedule dependent and daily administration was the most effective. KW2152 caused marginal activity against L1210 leukemia, B16 melanoma, and M5076 sarcoma. The effect on cultured cells suggested that KW2152 was not cross-resistant to Adriamycin (ADM) but was cross-resistant to mitomycin C (MMC); however, KW2152 caused prolongation of life span against mice bearing P388/ADM or P388/MMC. In tests against human tumors xenografted s.c. in nude mice, KW2152 significantly inhibited the growth of MX-1 mammary carcinoma with all tumors cured at i.v. doses of 4.4 mg/kg/day and p.o. doses of 26.2 mg/kg/day given daily for 7 days. KW2152 also inhibited distinct human gastric carcinomas, St-4 and St-15 tumors, and colon carcinoma Co-3 by daily administration for 7 days. Against St-4, KW2152 gave a treated versus control percentage of 27, compared to 52 for cis-diamminedichloroplatinum. Against Co-3, KW2152 was at least as effective as MMC, ADM, cis-diamminedichloroplatinum, and bleomycin, giving a treated versus control percentage of 18 at a dose of 8.6 mg/kg/day given daily for 7 days. KW2152 showed growth inhibitory activity against cultured murine tumors and human cells. The order of in vitro efficacy of KW2152 against murine tumors, P388 leukemia greater than L1210 leukemia, B16 melanoma, correlated with the order of the sensitivity on the i.p.-i.p. systems of these tumors. The 50% inhibitory concentrations against P388 leukemia cells were 5.3 X 10(-6) and 1.1 X 10(-7) M after 1 and 72 h exposure, respectively. KW2152 caused significant inhibition of RNA synthesis after a short time exposure. In P388 leukemia cells exposed for 1 h with KW2152, the 50% inhibitory concentration for RNA synthesis was 10(-5) M, 30-fold less than that for DNA synthesis. White blood cell depression or platelet depression was not significant after administration of the i.v. 10% lethal dose given daily for 7 days. Because of its good activity against human mammary tumor MX-1 and some effectiveness against other gastric and colon carcinomas and its water solubility, a novel antitumor antibiotic, KW2152, is being developed as a Phase I anticancer agent.
 ...
PMID:Antitumor activity of a novel antitumor antibiotic, quinocarmycin citrate (KW2152). 243 18

We have previously established that type I interferon (IFN), a mixture of alpha- and beta-IFN, augments the antitumor activity of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, against B16 melanoma. The objective of the present investigation was to extend these earlier observations to metastatic Lewis lung carcinoma and to determine specifically which component(s) of type I IFN potentiates the antitumor activity of DFMO. Furthermore, we wanted to determine whether type II (gamma) IFN can also potentiate the antitumor activity of DFMO. Treatment of animals bearing Lewis lung carcinoma with DFMO, 2% in drinking water (3 g/kg/day), or IFN-alpha/beta (1000 units/mouse) given subcutaneously on alternate days for a total of ten doses alone resulted in 42 and 5% inhibition of tumor growth, respectively. A combination of DFMO and interferon brought about complete elimination of tumors in 12 of the 18 animals, and 94% inhibition of tumor growth in the remainder. DFMO or type I IFN administered alone caused 94 and 26% inhibition of metastasis, respectively. Combination treatment with these two agents resulted in complete elimination of visible metastases. Treatment of mice bearing B16 melanoma with DFMO resulted in 81% inhibition of tumor growth compared to controls. The administration of interferons alone resulted in tumor growth inhibition of 15, 3, 1, and 43% for type I, alpha-, beta-, and gamma-interferons, respectively. Treatment of animals with combination of DFMO and various interferons resulted in inhibition of 94, 93, 86, and 94% of B16 tumor growth for type I, alpha-, beta-, and gamma-interferons, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of murine alpha-, beta-, and gamma-interferons in combination with alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, on the tumor growth and metastasis of B16 melanoma and Lewis lung carcinoma in mice. 249 64

We have previously shown that swainsonine, administered systemically to C57BL/6 mice, inhibited the pulmonary metastasis of iv injected B16-F10 melanoma cells by a mechanism involving interleukin-2 production and augmentation of natural killer cell activity. From this finding, which uses an "experimental metastasis" model system, we considered: (a) whether swainsonine would be effective in the inhibition of authentic or spontaneous metastasis; (b) whether the drug would also inhibit metastasis formation in organs other than the lungs; and (c) whether the drug would block the metastasis of tumor cells of different histological type or origin. Our data indicated that swainsonine effectively inhibited the spontaneous metastasis of B16-BL6 melanoma (by 88%) and M5076 reticulum sarcoma (by 95%) murine tumor cells to the lung and liver, respectively. In both cases, the antimetastatic activity of the drug increased as a function of the concentration in drinking water up to 3 micrograms/mL. These findings indicate that the antimetastatic activity of swainsonine is not limited to artificial or experimentally induced metastasis nor to a single tumor type or specific organ. The inhibition of metastasis is likely due to a combination of events, which are currently under investigation.
 ...
PMID:Swainsonine inhibition of spontaneous metastasis. 249 92

Swainsonine, a plant alkaloid and potent inhibitor of Asn-linked oligosaccharide processing, has previously been shown to inhibit organ colonization by metastatic murine tumor cells and to inhibit the growth of transformed fibroblasts in soft agar. In this report, we show that swainsonine has antiproliferative activity against human tumor cells growing in tissue culture and as tumor xenografts in nude mice. The antiproliferative activity of swainsonine was additive with that of human interferon-alpha 2 (HuIFN-alpha 2) in cultures of HT29 colon carcinoma, SN12 renal carcinoma, and A375 melanoma cells. In vivo, the growth rate of HT29m human colon carcinoma tumors in athymic nude mice was reduced by supplementing their drinking water with swainsonine (49%) or by administering HuIFN-alpha 2 systemically (53%); combining these treatments reduced tumor growth by 78%. Combining swainsonine and HuIFN-alpha 2 treatments enhanced the activity of the interferon-inducible enzyme 2',5'-oligoadenylate [2',5'-oligo(A)] synthetase in HT29m tumors compared to that observed in tumors from mice treated with interferon alone. In vitro, swainsonine enhanced interferon-dependent induction of 2',5'-oligo(A) synthetase activity in low-density cultures of HT29m cells. However, swainsonine alone did not stimulate 2',5'-oligo(A) synthetase activity in vivo or in vitro, indicating that the antiproliferative effect of swainsonine is independent of interferon production. The results suggest that in addition to the previously reported antimetastatic activity of swainsonine, the plant alkaloid has antiproliferative activity that is independent from, but additive with, that of interferon in vivo and in vitro.
 ...
PMID:Inhibition of human HT29 colon carcinoma growth in vitro and in vivo by swainsonine and human interferon-alpha 2. 249 93

Researchers have suggested that the increased longitudinal relaxation rates (1/T1) of solvent water protons often found in melanoma result either from the paramagnetism of stable free radicals occurring in melanin or from that of methemoglobin in nonacute hemorrhagic regions of the tumor. However, field-cycling relaxometry and model solutions of synthetic melanin produced data which show that free radicals in melanin do not contribute significantly to 1/T1; instead, aggregation of melanin into macromolecular particles and binding of biologically-common paramagnetic metal ions (ie Fe3+, Mn2+, and Cu2+) to melanin effectively do increase 1/T1. These data have been combined with published histochemical data on melanin-containing tissues, while disregarding any additional effect related to hemorrhage. The result indicates that in melanoma the expected contribution of melanin-bound Fe3+ to 1/T1, at typical imaging fields, predominates under estimated in vivo conditions; furthermore, the total contribution from all sources, specifically due to the presence of melanin, is sufficient to account for reported measurements of 1/T1 in melanoma. Comparing the latter results with published data on T1 relaxation in model solutions of methemoglobin suggests that co-existing regions of nonacute microhemorrhage also may contribute significantly to 1/T1 under certain conditions. Finally, the implications for 1/T2 of melanin occurring in vivo within discrete melanosomes is discussed.
 ...
PMID:Sources of the increased longitudinal relaxation rates observed in melanotic melanoma. An in vitro study of synthetic melanins. 250 76

The anti-tumour properties of Cy 233, a new nitrosoureido sugar, were investigated in two murine solid tumours: B16 melanoma and subcutaneously implanted colon adenocarcinoma. Injected i.v., Cy 233 exerted a strong anti-tumour effect against the established B16 melanoma: long-term survivors were recorded with all schedules of treatment. The drug was even more effective against advanced colon 38 adenocarcinoma: it produced a high percentage of total tumour regression, regardless of the route of administration (i.p., i.v., p.o.). The marked in vivo activity of Cy 233 against advanced colon 38 adenocarcinoma, which is known to be resistant to such major anti-cancer drugs as BCNU and chlorozotocin, its water solubility and its stability in aqueous media are further elements warranting toxicological and clinical studies of this agent.
 ...
PMID:Characterization of the anti-tumour activity against solid tumours of a new nitrosoureido sugar: Cy 233. 259 12

Fotemustine (S 10036) is a new nitrosourea compound whose antitumoral activity has been demonstrated, particularly in disseminated malignant melanoma. Pharmacokinetic parameters of this drug were investigated during phase II clinical trials and compared according to tumor type. Twenty-six patients entered the study and received an induction treatment (weekly 100 mg/sq.m of fotemustine in 250 ml of 5% glucose in water over a one-hour IV infusion for 3 consecutive weeks) followed by a 4-week rest period. A maintenance therapy (100 mg/sq.m every three weeks) was proposed in stabilized or responsive patients. Plasmatic assay of fotemustine was carried out by HPLC. Seventy-one cycles were analyzed. A short half-life and a large intra and inter-individual variability of all kinetic parameters (especially plasmatic clearance) was found independent of tumour type. The study of patient's clinical behaviour was shown to be related to the clearance value obtained during the first treatment cycle which seems to predict the clinical response in the case of malignant melanoma. This finding needs to be confirmed in a larger number of patients and in other tumor localizations.
 ...
PMID:[Study of the clinical pharmacokinetics of fotemustine in various tumor indications]. 263 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>