Dacarbazine: An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564)Melanoma: A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445)Vinblastine: Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors.Mechlorethamine: A biologic alkylating agent that exerts its cytotoxic effects by forming DNA ADDUCTS and DNA interstrand crosslinks, thereby inhibiting rapidly proliferating cells. The hydrochloride is an antineoplastic agent used to treat HODGKIN DISEASE and LYMPHOMA.Hodgkin Disease: A malignant disease characterized by progressive enlargement of the lymph nodes, spleen, and general lymphoid tissue. In the classical variant, giant usually multinucleate Hodgkin's and REED-STERNBERG CELLS are present; in the nodular lymphocyte predominant variant, lymphocytic and histiocytic cells are seen.Antineoplastic Agents, Alkylating: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)Procarbazine: An antineoplastic agent used primarily in combination with mechlorethamine, vincristine, and prednisone (the MOPP protocol) in the treatment of Hodgkin's disease.Antineoplastic Combined Chemotherapy Protocols: The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Skin Neoplasms: Tumors or cancer of the SKIN.Vincristine: An antitumor alkaloid isolated from VINCA ROSEA. (Merck, 11th ed.)Nitrosourea CompoundsNimustine: Antineoplastic agent especially effective against malignant brain tumors. The resistance which brain tumor cells acquire to the initial effectiveness of this drug can be partially overcome by the simultaneous use of membrane-modifying agents such as reserpine, calcium antagonists such as nicardipine or verapamil, or the calmodulin inhibitor, trifluoperazine. The drug has also been used in combination with other antineoplastic agents or with radiotherapy for the treatment of various neoplasms.Carmustine: A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)Mesna: A sulfhydryl compound used to prevent urothelial toxicity by inactivating metabolites from ANTINEOPLASTIC AGENTS, such as IFOSFAMIDE or CYCLOPHOSPHAMIDE.Lomustine: An alkylating agent of value against both hematologic malignancies and solid tumors.Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells. In addition to antiviral activity, it activates NATURAL KILLER CELLS and B-LYMPHOCYTES, and down-regulates VASCULAR ENDOTHELIAL GROWTH FACTOR expression through PI-3 KINASE and MAPK KINASES signaling pathways.Combined Modality Therapy: The treatment of a disease or condition by several different means simultaneously or sequentially. Chemoimmunotherapy, RADIOIMMUNOTHERAPY, chemoradiotherapy, cryochemotherapy, and SALVAGE THERAPY are seen most frequently, but their combinations with each other and surgery are also used.Prednisone: A synthetic anti-inflammatory glucocorticoid derived from CORTISONE. It is biologically inert and converted to PREDNISOLONE in the liver.O(6)-Methylguanine-DNA Methyltransferase: An enzyme that transfers methyl groups from O(6)-methylguanine, and other methylated moieties of DNA, to a cysteine residue in itself, thus repairing alkylated DNA in a single-step reaction. EC Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.Chills: The sudden sensation of being cold. It may be accompanied by SHIVERING.Benzenesulfonates: Organic salts and esters of benzenesulfonic acid.Survival Analysis: A class of statistical procedures for estimating the survival function (function of time, starting with a population 100% well at a given time and providing the percentage of the population still well at later times). The survival analysis is then used for making inferences about the effects of treatments, prognostic factors, exposures, and other covariates on the function.Hexanones: 6-carbon straight-chain or branched ketones.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Tamoxifen: One of the SELECTIVE ESTROGEN RECEPTOR MODULATORS with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the ENDOMETRIUM.Neoplasm Metastasis: The transfer of a neoplasm from one organ or part of the body to another remote from the primary site.Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant.Administration, Intravenous: Delivery of substances through VENIPUNCTURE into the VEINS.Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.Drug Administration Schedule: Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience.Neoplasm Staging: Methods which attempt to express in replicable terms the extent of the neoplasm in the patient.Phenylurea Compounds: Compounds that include the amino-N-phenylamide structure.Niacinamide: An important compound functioning as a component of the coenzyme NAD. Its primary significance is in the prevention and/or cure of blacktongue and PELLAGRA. Most animals cannot manufacture this compound in amounts sufficient to prevent nutritional deficiency and it therefore must be supplemented through dietary intake.Etoposide: A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.Vindesine: Vinblastine derivative with antineoplastic activity against CANCER. Major side effects are myelosuppression and neurotoxicity. Vindesine is used extensively in chemotherapy protocols (ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS).Ifosfamide: Positional isomer of CYCLOPHOSPHAMIDE which is active as an alkylating agent and an immunosuppressive agent.DNA Modification Methylases: Enzymes that are part of the restriction-modification systems. They are responsible for producing a species-characteristic methylation pattern, on either adenine or cytosine residues, in a specific short base sequence in the host cell's own DNA. This methylated sequence will occur many times in the host-cell DNA and remain intact for the lifetime of the cell. Any DNA from another species which gains entry into a living cell and lacks the characteristic methylation pattern will be recognized by the restriction endonucleases of similar specificity and destroyed by cleavage. Most have been studied in bacterial systems, but a few have been found in eukaryotic organisms.Organophosphorus Compounds: Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS.Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods.Melanoma, Experimental: Experimentally induced tumor that produces MELANIN in animals to provide a model for studying human MELANOMA.Kaplan-Meier Estimate: A nonparametric method of compiling LIFE TABLES or survival tables. It combines calculated probabilities of survival and estimates to allow for observations occurring beyond a measurement threshold, which are assumed to occur randomly. Time intervals are defined as ending each time an event occurs and are therefore unequal. (From Last, A Dictionary of Epidemiology, 1995)Interleukin-2: A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes.GuanineRemission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level.Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis.Pheochromocytoma: A usually benign, well-encapsulated, lobular, vascular tumor of chromaffin tissue of the ADRENAL MEDULLA or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of EPINEPHRINE and NOREPINEPHRINE, is HYPERTENSION, which may be persistent or intermittent. During severe attacks, there may be HEADACHE; SWEATING, palpitation, apprehension, TREMOR; PALLOR or FLUSHING of the face, NAUSEA and VOMITING, pain in the CHEST and ABDOMEN, and paresthesias of the extremities. The incidence of malignancy is as low as 5% but the pathologic distinction between benign and malignant pheochromocytomas is not clear. (Dorland, 27th ed; DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1298)

Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. (1/1313)

The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.  (+info)

Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. (2/1313)

DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase (PARP) are activated by DNA strand breaks and participate in DNA repair. We investigated the interactive effects of inhibitors of these enzymes [wortmannin (WM), which inhibits DNA-PK, and 8-hydroxy-2-methylquinazolin-4-one (NU1025), a PARP inhibitor] on cell survival and DNA double-strand break (DSB) and single-strand break (SSB) rejoining in Chinese hamster ovary-K1 cells following exposure to ionizing radiation (IR) or temozolomide. WM (20 microM) or NU1025 (300 microM) potentiated the cytotoxicity of IR with dose enhancement factors at 10% survival (DEF10) values of 4.5 +/- 0.6 and 1.7 +/- 0.2, respectively. When used in combination, a DEF10 of 7.8 +/- 1.5 was obtained. WM or NU1025 potentiated the cytotoxicity of temozolomide, and an additive effect on the DEF10 value was obtained with the combined inhibitors. Using the same inhibitor concentrations, their single and combined effects on DSB and SSB levels following IR were assessed by neutral and alkaline elution. Cells exposed to IR were post-incubated for 30 min to allow repair to occur. WM or NU1025 increased net DSB levels relative to IR alone (DSB levels of 1.29 +/- 0.04 and 1.20 +/- 0.05, respectively, compared with 1.01 +/- 0.03 for IR alone) and the combination had an additive effect. WM had no effect on SSB levels, either alone or in combination with NU1025. SSB levels were increased to 1.27 +/- 0.05 with NU1025 compared with IR alone, 1.02 +/- 0.04. The dose-dependent effects of the inhibitors on DSB levels showed that they were near maximal by 20 microM WM and 300 microM NU1025. DSB repair kinetics were studied. Both inhibitors increased net DSB levels over a 3 h time period; when they were combined, net DSB levels at 3 h were identical to DSB levels immediately post-IR. The combined use of DNA repair inhibitors may have therapeutic potential.  (+info)

Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. (3/1313)

PURPOSE: The combination of chemotherapy with immunotherapeutic agents such as interleukin-2 and interferon alfa-2b has been reported to provide improved treatment results in patients with metastatic melanoma, compared with the use of chemotherapy alone. We have performed a prospective randomized trial in patients with metastatic melanoma, comparing treatment with chemotherapy to treatment with chemoimmunotherapy. PATIENTS AND METHODS: One hundred two patients with metastatic melanoma were prospectively randomized to receive chemotherapy composed of tamoxifen, cisplatin, and dacarbazine or this same chemotherapy followed by interferon alfa-2b and interleukin-2. Objective responses, survival, and toxicity in the two groups were evaluated at a median potential follow-up of 42 months. RESULTS: In 52 patients randomized to receive chemotherapy, there were 14 objective responses (27%), including four complete responses. In 50 patients randomized to receive chemoimmunotherapy, there were 22 objective responses (44%) (P2 = .071), including three complete responses. In both treatment groups, the duration of partial responses was often short, and there was a trend toward a survival advantage for patients receiving chemotherapy alone (P2 = .052; median survival of 15.8 months compared with 10.7 months). Treatment-related toxicities were greater in patients receiving chemoimmunotherapy. CONCLUSION: With the treatment regimens used in this study, the addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols showing the benefit of this treatment strategy.  (+info)

Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. (4/1313)

PURPOSE: The primary objective of this clinical study was to assess the feasibility of administering recombinant interleukin-2 and recombinant interferon alfa-2a before and after combination cytotoxic chemotherapy. After encouraging initial responses, the study was expanded to further evaluate the therapeutic potential, clarify the toxicities of this regimen, and explore any associated immunologic changes. PATIENTS AND METHODS: Eighty-four patients with metastatic melanoma, including patients with brain metastases, were treated on this 6-week protocol. Patients received combination cisplatin (25 mg/m2/d) and dacarbazine (220 mg/m2/d) on days 1 through 3 and 22 through 24 plus carmustine (150 mg/m2) on day 1. Interleukin 2 (13.5 million IU/m2/d) and interferon alfa (6 MU/m2/d) were administered on days 4 through 8 and 17 through 21. RESULTS: Among 83 patients assessable for response, 12 complete and 34 partial responses were documented (55% response rate). The median time to disease progression was 7 months, the median survival from study entry was 12.2 months, and the median survival from diagnosis of metastatic disease was 15.5 months. Although patients were hospitalized to receive treatment, intensive care unit support generally was not needed. Dose-limiting toxicities were related to elevations in serum bilirubin and serum creatinine levels. No patient developed a grade 4 clinical toxicity. Treatment produced a skin depigmentation, which was associated with prolonged survival. CONCLUSION: A plateau in both the survival and time to progression curves beyond 2 years (15% of the patients) and a greater than 10% disease-free survival beyond 4 years indicate that there may be a long-term benefit for some patients. The limited toxicity of this regimen should permit its use in most oncology settings. A randomized trial of chemoimmunotherapy versus chemotherapy should be performed to establish the value of chemoimmunotherapy for melanoma.  (+info)

Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. (5/1313)

Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.  (+info)

Treatment of neoplastic meningitis with intrathecal temozolomide. (6/1313)

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (i.t.) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct i.t. use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an i.t. agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 micromol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the i.t. administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.  (+info)

DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents. (7/1313)

We have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransferase activity, suggesting that Mgmt constitutes the major, if not the only, O6-methylguanine DNA methyltransferase. Primary mouse embryo fibroblasts and bone marrow cells from Mgmt -/- mice were significantly more sensitive to the toxic effects of the chemotherapeutic alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin and temozolomide than those from Mgmt wild-type mice. As expected, Mgmt-deficient fibroblasts and bone marrow cells were not sensitive to UV light or to the crosslinking agent mitomycin C. In addition, the 50% lethal doses for Mgmt -/- mice were 2- to 10-fold lower than those for Mgmt +/+ mice for 1,3-bis(2chloroethyl)-1-nitrosourea, N-methyl-N-nitrosourea and streptozotocin; similar 50% lethal doses were observed for mitomycin C. Necropsies of both wild-type and Mgmt -/mice following drug treatment revealed histological evidence of significant ablation of hematopoietic tissues, but such ablation occurred at much lower doses for the Mgmt -/- mice. These results demonstrate the critical importance of O6-methylguanine DNA methyltransferase in protecting cells and animals against the toxic effects of alkylating agents used for cancer chemotherapy.  (+info)

A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies. (8/1313)

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.  (+info)

  • To determine the overall tumor response rate to imatinib mesylate in combination with capecitabine and dacarbazine as first line and second line therapy in advanced metastatic medullary thyroid carcinoma. (clinicaltrials.gov)
  • We conclude that dacarbazine is genotoxic and cytotoxic to the mouse testis in a transient fashion, and these effects are exerted along with decrease in testosterone and increase in lactate dehydrogenase levels in the testis. (elsevier.com)
  • Dacarbazine induced both head and tail abnormalities and some sperms with cytoplasmic droplets, but significant increase was seen in all dose groups on days 14 and 21, and at 100 mg/kg dose-level on day 35. (elsevier.com)
  • There was no particular dose-response of dacarbazine on any parameters tested. (elsevier.com)
  • If you are found to be eligible to take part in this study, you will begin treatment with imatinib mesylate, capecitabine, and dacarbazine. (clinicaltrials.gov)
  • The first group of study participants will receive lower doses of imatinib mesylate, capecitabine and dacarbazine. (clinicaltrials.gov)
  • Swiss albino mice (9-12 weeks old) were treated with 0, 5, 25, 50, or 100 mg/kg body weight/day dacarbazine (i.p.) for 5 days at intervals of 24 h between treatments. (elsevier.com)
  • Overall, 1) PNT2258+docetaxel produced a greater than additive effect compared to single agents, 2) PNT2258+dacarbazine was not superior to PNT2258 alone, 3) PNT2258+vemurafenib while highly active, was not superior to vemurafinib therapy alone, and 4) therapeutic PNT2258 exposures have been attained in patients. (aacrjournals.org)
  • Our data reveal in situ changes in melanoma metastases during treatment with sorafenib and dacarbazine and suggest an additional mechanism of action through immunomodulation. (uzh.ch)
  • Dacarbazine (5-(3,3-dimethyl-triazeno) imidazole-4-carboxamide), 3 and 6 mM, was toxic to SECs but not to hepatocytes. (aspetjournals.org)
  • Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. (selfdecode.com)
  • Price of Dacarbazine EP Impurity C, VENDOR OF Dacarbazine IMPURITIES, CAS: NA, 5-diazenyl-1H-imidazole-4-carboxamide SUPPLIER, Dacarbazine impurity manufacturer. (synthinkchemicals.com)
  • This study presents data indicating that nanomolar concentrations of the hormonally active form of vitamin D, 1α,25‑dihydroxyvitamin D3 [1α,25(OH)2D its non‑calcemic analogues 20S‑hydroxyvitamin D3 and 21‑hydroxypregnacalciferol, as well as the low‑calcemic synthetic analog calcipotriol, modulate the efficacy of the anticancer drugs cisplatin and dacarbazine. (spandidos-publications.com)
  • On the other hand, only 1α,25(OH)2D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. (spandidos-publications.com)
  • Notably, cisplatin (300 µM) exhibited a higher overall antiproliferative activity than dacarbazine. (spandidos-publications.com)
  • Finally, cisplatin, dacarbazine and 1α,25(OH)2D3 displayed modulatory effects on the expression of ROS and vitamin D‑associated genes in the melanoma A375 cells. (spandidos-publications.com)
  • Patients received cisplatin, vinblastine, and dacarbazine (CVD: cisplatin (20 mg/m 2 ) and vinblastine (1.2 mg/m 2 ) on days 1-4, dacarbazine (800 mg/m 2 ) on day 1 only) concurrently with interleukin 2 (9 MIU/m 2 /day) by continuous i.v. infusion on days 1-4 and IFN-α (5 MU/m 2 /day) on days 1-5, 8, 10, and 12. (aacrjournals.org)
  • Dacarbazine was proven to be just as efficacious as procarbazine in the German trial for paediatric Hodgkin's lymphoma, without the teratogenic effects. (wikipedia.org)
  • When dacarbazine is used to treat Hodgkin's lymphoma is may be injected once a day for 5 days in a row every 4 weeks or it may be injected once every 15 days. (medlineplus.gov)
  • The usual recommended dosage of dacarbazine for treating Hodgkin's disease is 150 mg per m 2 daily for 5 days. (emedtv.com)
  • When used to treat Hodgkin's lymphoma, dacarbazine is used in combination with other medicines, regardless of the amount used. (emedtv.com)
  • Interpretation: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. (mdc-berlin.de)
  • These studies were undertaken to determine the initial cellular target and the role of glutathione detoxification of dacarbazine, a toxin implicated in hepatic veno-occlusive disease. (aspetjournals.org)
  • You will be given dacarbazine in the chemotherapy day unit or during a stay in hospital. (macmillan.org.uk)
  • You should not be given dacarbazine if you are pregnant or intend to become pregnant. (mydr.com.au)
  • abstract = "Background: Dacarbazine is an antitumour drug used with considerable success in the chemotherapy of a number of human neoplasias, particularly advanced disseminated melanoma. (elsevier.com)
  • Tell your doctor if you have ever had any unusual or allergic reaction to dacarbazine or any other medicines. (drugster.info)
  • Dacarbazine, Westren Medicine, Western Drug manufacturer / supplier in China, offering 99.6% High Purity Powder Daunorubicin Hydrochloride (CAS: 23541-50-6) 20mg, High Purity Sertraline HCl Sertraline Hydrochloride 79559-97-0 Tablet and Capsule Garde, Hydrocortisone Sodium Succinate Powder for Injection GMP Factory FDA Approved and so on. (made-in-china.com)
  • Your doctor will order certain tests to check your body's response to dacarbazine. (medlineplus.gov)
  • Dacarbazine can cause anemia and reduce the body's ability to fight infections. (dvohmg.com)
  • There are also generic versions of dacarbazine available from APP, Bedford, Mayne Pharma (now Hospira) and Teva. (wikipedia.org)
  • NDA 075940 describes DACARBAZINE , which is a drug marketed by Abraxis Pharm , Fresenius Kabi Usa , Hospira , Teva Pharms Usa , and West-ward Pharms Int , and is included in six NDAs. (drugpatentwatch.com)
  • hospira inc. received approval authorities for arresting its dacarbazine modified capsules in early january, but the company has reportedly needed considerable time to build oneself up an adequate supply of the drug growing and to reach in thee a comarketing agreement with another large pharmaceutical manufacturer. (victoriangraceart.com)