Disease relevance of DTIC-Dome

• Animals whose tumors were treated by intralesional injection of decarbazine (DTIC) or saline showed progressive tumor growth and metastasis resulting in death within 120 days of tumor implantation [1].
• These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC [2].
• DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable [2].
• Eosinophilia with DTIC chemotherapy [3].
• In light of the relatively modest toxicity observed with this regimen, the combination of DBDT represents a reasonable alternative to single-agent DTIC as first-line therapy for patients with metastatic melanoma [4].

High impact information on DTIC-Dome

• Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously [2].
• Single and multiple intraperitoneal injections of DTIC did not alter organ specificity [2].
• Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity [2].
• PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma [5].
• As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial [5].

Chemical compound and disease context of DTIC-Dome

• PURPOSE: Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone [6].
• (BALB/c X DBA/2) F1 (hereafter called CD2F1) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F1 lymphocytes [7].
• RESULTS: Numerous articles have reported an overall response rate of 47% (95% confidence limit, 39.25 to 54.75) when patients with metastatic melanoma are treated with the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and TAM (DBDT) [4].
• CONCLUSION: While TAM as a single agent is minimally active in treating patients with metastatic melanoma, when it is combined with DTIC, BCNU, and DDP, a marked improvement in the overall response rate is observed [4].
• CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma [8].

Biological context of DTIC-Dome

• In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells [7].
• The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro [9].
• ATase levels in PBMCs were used as a surrogate for tumour ATase depletion to determine whether this correlated with either the pharmacokinetics of DTIC and its major metabolite AIC or other clinical sequelae [10].
• We assessed whether split dosing with the methylating agent DTIC is an effective strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in order to decrease tumour resistance to BCNU [10].
• In line with these results, we observed a nearly 3-fold increase of apoptosis for the combination of thalidomide and DTIC compared with the rate of apoptotic cells in DTIC-only-treated melanoma xenotransplants [11].

Anatomical context of DTIC-Dome

• Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes [9].
• PURPOSE: In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide [12].
• A triazene-xenogenized tumor sub-line was derived from the mouse mastocytoma cell line P815 following several transplant generations in vivo on DTIC [13].
• In addition to previous evidence for a role of L3T4+ T cells in the protective anti-parental tumor immunity induced by xenogenized variant cells of a murine lymphoma (L5178Y/DTIC), we have investigated the possible participation in this effect of L5178Y tumor-specific lymphocytes of the Lyt-2+ T cell subset [14].
• Administration of anti-IFN-gamma MAb in vivo significantly impaired the resistance of L5178Y/DTIC-immune mice to challenge with parental cells, as manifested by survival criteria and increased tumor-cell proliferation in the spleens of antibody-treated mice [14].

Associations of DTIC-Dome with other chemical compounds

• Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days [15].
• The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals [16].
• PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment [17].
• The four-drug chemotherapy regimen was as follows: dacarbazine (DTIC) 200 mg/m2 days 1 to 5, vincristine 1 mg/m2 days 1 and 4, bleomycin 15 mg days 2 and 5 intravenously (IV), and lomustine (CCNU) 80 mg day 1 orally [18].
• Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC [8].

Gene context of DTIC-Dome

• Antihuman CYP1A2 antiserum also inhibited DTIC N-demethylation [19].
• The Km (Vmax) values for metabolism of DTIC by recombinant human CYP1A1 and CYP1A2 were 595 microM (0.684 nmol/min/mg protein) and 659 microM (1.74 nmol/min/mg protein), respectively [19].
• We now report that the DTIC N-demethylation involved in MTIC formation by human liver microsomes is catalyzed by CYP1A1, CYP1A2, and CYP2E1 [19].
• We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters [20].
• However, there was no significant correlation of MMR expression alone or combined with MGMT levels with clinical response to DTIC-based chemotherapy in metastatic melanoma [21].

Analytical, diagnostic and therapeutic context of DTIC-Dome

• However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug [7].
• It has not yet been conclusively proven that combination chemotherapy yields superior results to single agent dacarbazine (DTIC) [which has for many years formed the cornerstone of therapy] [22].
• When abrin was given together with DTIC, the effect on the two xenografts tested was superior to that of each agent given alone [23].
• In this species, single doses of DTIC could profoundly depress antilymphoma allograft resistance as well as the number of antibody-producing cells after primary and secondary stimulation with sheep erythrocytes [24].
• Intra-arterial infusion of chemotherapeutic agents (CDDP alone or combined with DTIC) was used to treat recurrent melanoma in 22 patients [25].

References