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

Introduction of the anticancer drug dacarbazine is the result of an attempt to design antagonists of purine biosynthesis. The mechanism of action of dacarbazine depends mainly on enzymatic transformation into as yet unknown reactive (electrophilic) intermediates. Recent studies have led to the identification and synthesis of 5-(3-hydroxymethyl-3-methyl)imidazole-4-carboxamide (HMTIC), a carbinolamine metabolite with methylating capacity. Although dacarbazine and related cytostatic triazenes are effective in the treatment of malignant melanoma and other human malignancies, dacarbazine has been demonstrated to be a carcinogen in laboratory rodents. Chronic administration of dacarbazine to rats of each sex induced predominantly thymic lymphosarcomas and mammary adenocarcinomas that were transplantable. Intraperitoneally injected 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), a metabolite of dacarbazine, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Animals treated with 5-diazoimidazole-4-carboxamide developed a low incidence of thymic, stomach, bladder or mammary tumours. Animals receiving 5-aminoimidazole-4-carboxamide developed a variety of tumours. No secondary malignancy has been reported in humans after treatment with dacarbazine alone. Despite their adverse effects, dacarbazine and related cytostatic triazene derivatives are useful clinically since their haematological toxicity is relatively moderate. As a rule, they are not cross-resistant with nitrogen mustard alkylating agents. It is hoped that research and development of second-generation N-(1-hydroxyalkyl)triazene compounds will lead to improvements in their clinical efficacy.
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PMID:Carcinogenicity of cytostatic triazenes. 358 85

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74

The antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III) against the P388 leukemia and against the B16 melanoma was investigated. The test compound showed high activity against these tumor models. The tumor inhibiting effect was in the range or better than the effects of the compounds cyclophosphamide, cisplatin, or 5-fluorouracil, which were tested as positive controls. The effective substance is a new, water soluble, anionic, nitrogen-heterocyclic coordinated, ruthenium species, exhibiting antitumor activity.
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PMID:Antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III). A representative of a new class of inorganic antitumor agents. 370 Apr 62

A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m2 per day for 5 days and repeated every 21-28 days. The patient population had a median age of 55 years (range 38-76) and a median Karnofsky performance status of 80 (range 60-100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/microliter (range 100-4800) in 8 heavily pretreated patients treated at 350 mg/m2 per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m2 and had WBC nadirs of 800/microliter and 600/microliter. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m2 per day, nadir 85,000/microliter). Neither hyponatremia nor symptomatic hypo-osmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m2 per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09-6.79 micrograms/ml. Steady state was achieved in 14.5 +/- 5.9 h (mean +/- SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t 1/2 of 5.3 +/- 3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543 +/- 150 micrograms/ml h and reflected a cyclophosphamide total-body clearance (CLTB) of 103 +/- 31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6-4.3 micrograms/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3% +/- 7.6% and 15.1% +/- 2.0% of the administered daily dose, respectively. The t1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m2 as an i.v. bolus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion. 375 57

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.
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PMID:Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents. 377 45

Forty-two patients with intransit metastases of melanoma in a limb were treated by isolated regional perfusion chemotherapy using mechlorethamine (nitrogen mustard). Group 1 (n = 12) underwent treatment at low dose, less than 0.35 mg/kg, or low temperature, less than 38 degrees C. Group 2 (n = 30) received higher doses, 0.35 to 0.6 mg/kg, plus heat at 38 degrees C to 41 degrees C. No patient had evidence of disease outside the limb at the time of perfusion. The median follow-up time was 48 months (range, 1 to 9 years). Of the 42 patients, 29 had measurable lesions that responded as follows: group 1, complete response (CR) in two of ten and partial response (PR) in none; group 2, CR in six of 19 and PR in six of 19. The combined CR and PR rate of 12 of 19 in group 2 was significantly higher than that of group 1 (P less than .05). CR lasted only 2 months in the two patients of group 1, but persisted in the six patients of Group 2, four of whom are still alive free of disease at 16, 21, 33, and 40 months. Relapse-free control of disease in the limb was achieved in 36% of the patients in group 2 at 24 months, compared with 0% in group 1 (P less than .05). An overall survival of 74% at 48 months was observed in group 2, significantly higher than that of 64% for group 1 (P less than .05). The status of the regional lymph nodes (RLN) and the number of metastases did not affect tumor response. However, 77% of RLN-negative patients survived 48 months, in contrast to only 38% of RLN-positive patients (P less than .05). One patient died postoperatively of myocardial infarction. No serious systemic toxicity developed. Two patients who underwent repeat salvage perfusions developed a reversible peripheral neuropathy in the limb. Limb function was good after treatment, and dramatically improved in patients who had advanced satellitosis that responded to treatment. These results suggest that heated limb perfusion using mechlorethamine at an adequate dose can offer long-term control of intransit metastases in approximately one third of these patients, with preservation of good limb function and possible prolongation of survival.
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PMID:Regional isolated limb perfusion of melanoma intransit metastases using mechlorethamine (nitrogen mustard). 378 5

We studied the immediate effects of rapid freezing on 19 variously sized uveal melanomas that were subjected to cryoenucleation using liquid nitrogen and a cryoring by light and electron microscopy and tissue culture. The freezing time and the temperature of 11 lesions were recorded. The light microscopic finding of an intranuclear clear center with peripheral displacement of clumped chromatin against the nuclear membrane was suggestive of intranuclear ice crystal formation but did not indicate cellular death of the tumors. The major ultrastructural changes, including plasmalemmal breaks, dissolution of cytoplasmic matrix, and damage to various organelles, however, suggested acute necrosis in tumors not exceeding 7 mm in elevation. Failure of the melanoma cells to grow in tissue culture and positive staining with trypan blue support the contention of tumor death. The late effects of rapid freezing were also evaluated in another case of uveal melanoma. The eye was enucleated six months after cryopexy. Histopathologic findings showed that the tumor was necrotic. Failure of the neoplasm to regress (noted clinically) was related to edema and inflammatory infiltrates.
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PMID:The effect of rapid freezing on uveal melanomas. 379 91

We have previously reported that chloroethyl nitrosourea and nitrogen mustard bone marrow toxicity can be selectively reduced by placement of the cytotoxic group on specific positions of a glucose molecule. We have now synthesized and evaluated a new drug in which the mustard cytotoxic group is attached to the carbon-6 position of galactose (C6-GLM). C6-GLM, administered i.p. as a single 10% lethal dose of 15.5 mg/kg, produced a 121% increase in life span (ILS) in mice bearing the ascitic P388 leukemia, compared to a 60% ILS with a 10% lethal dose of nitrogen mustard (P less than 0.01). A single p.o. dose of C6-GLM, 16 mg/kg, produced an ILS of 58%. Against i.p.-implanted B-16 melanoma, i.p. C6-GLM produced a 56% ILS compared to 30% with an equitoxic dose of nitrogen mustard (P less than 0.01). The activity of the two drugs for Ehrlich ascites was comparable, with 60% survivors with the galactose mustard. A single 10% lethal dose of C6-GLM reduced the white blood cells to 74% of control; circulating granulocytes remained at 91% of initial values. With nitrogen mustard, the nadir white blood cell count was 57% of control with an absolute granulocyte count of 70% of initial values (P less than 0.01). The toxicity of melphalan was considerably greater, with a lower and more protracted while blood cell nadir and an absolute neutrophil count nadir of 49% of control. These findings paralleled the relative decrements in bone marrow DNA synthesis produced by the three drugs. Measurement of human bone marrow granulocyte-macrophage colony-forming units, following in vitro exposure to graded concentrations of the three mustards, confirmed the bone marrow sparing properties of C6-GLM. At the highest concentration, 1 X 10(-2) mM, the latter drug produced only a 33% reduction in colonies compared to a 75% reduction with nitrogen mustard and a virtual elimination of activity of colony-forming units with melphalan. The demonstration of antitumor activity, at least equivalent to nitrogen mustard, without the necessity of significant bone marrow toxicity supports the development of C6-GLM for clinical trials in humans.
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PMID:6-[Bis(2-chloroethyl)amino]-6-deoxygalactopyranose hydrochloride (C6-galactose mustard), a new alkylating agent with reduced bone marrow toxicity. 380 75

6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule.
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PMID:In vitro comparative studies of the myelotoxicity and antitumor activity of 6-[bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose versus melphalan utilizing the CFU-C and HTSCA assays. 394

Previous studies indicate dietary phenylalanine and tyrosine restriction may be of value in managing advanced cancer patients. To further evaluate this approach, we performed a 60-day study in which four patients with advanced malignant melanoma received formula diets via nasogastric tube containing only 8 mg total phenylalanine and tyrosine per kg lean body mass per day. Two of three patients completing elemental balance studies were in negative nitrogen, potassium, and phosphorus balance, suggesting an essential nutrient deficiency. Three patients tolerated the diet well, but one was non-compliant. Although no serious toxicity developed, serum albumin, total iron binding capacity and cholesterol significantly decreased (p less than 0.01) in the three complaint patients. Fasting plasma phenylalanine and tyrosine values did not significantly change during the study, but two-hour postprandial plasma phenylalanine and tyrosine concentrations fell below normal and were significantly lower than preprandial levels (p less than 0.01). There were no tumor responses.
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PMID:The effect of a phenylalanine and tyrosine restricted diet on elemental balance studies and plasma aminograms of patients with disseminated malignant melanoma. 396 27


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