Antitumour imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumor agent

Stevens, Malcolm F. G.; Hickman, John A.; Stone, R. L.; Gibson, Neil W.; Baig, Ghouse Unissa; Lunt, E.; Newton, Christopher G.

doi:10.1021/jm00368a016

Cited by 210 publications

(112 citation statements)

References 6 publications

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“…Interestingly that patient had just failed treatment with temozolomide, an oral alkylating agent. 23 Graft failures prompted an increase in the intensity of the preparative regimen in subsequent patients. Near complete donor engraftment by day 30 (490% donor chimerism) was present in 6/18 (33%) evaluable transplants, with 3/6 (50%) of these patients developing 4grade 1 acute GVHD whereas no other patients had significant acute GVHD (P ¼ 0.025).…”

Section: Chimerismmentioning

confidence: 99%

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience

Artz

Besien

Zimmerman

et al. 2004

Bone Marrow Transplant

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Summary:Nonmyeloablative allogeneic stem cell transplantation (NST) has considerable activity in patients with metastatic renal cell carcinoma (RCC), although there are limited long-term follow-up data. Between February 1999 and May 2003, 18 patients with metastatic RCC underwent 19 matched-sibling NSTs after conditioning with fludarabine and cyclophosphamide with tacrolimus and mycophenolate mofetil as posttransplant immunosuppression. Among the four objective responses, all were partial and have relapsed with a median response duration of 609 days (range, 107-926). All responders are alive at a median of 41 months. Median overall survival for the entire cohort was 14 months. There were four early treatment-related deaths and one late treatment-related death. Eight patients died from progressive disease and five (28%) from treatment-related mortality. Stratifying transplant outcome as early death, intermediate (no response, no early death), or response, the combination of pre-treatment anemia and decreased performance status, was associated with adverse outcome (P ¼ 0.015) and reduced survival (HR 5.4, 95% confidence interval of 1.4 to 21, P ¼ 0.007). Responders demonstrated prolonged survival compared to nonresponders (P ¼ 0.002). NST leads to durable responses in a minority of metastatic RCC patients. Appropriate patient selection is paramount. Anemia and decreased performance status may enable risk stratification.

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Section: Chimerismmentioning

confidence: 99%

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience

Artz

Besien

Zimmerman

et al. 2004

Bone Marrow Transplant

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“…3,4 TMZ has several advantages over other existing alkylating agents because of its unique characteristics. [5][6][7][8] Because TMZ is a small lipophilic molecule with a molecular weight of 194 Da, it can be administered orally and it crosses the blood-brain barrier effectively. The levels of TMZ in the brain or cerebrospinal fluid are about 30-40% of the plasma concentration.…”

Section: Introductionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 lM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein lightchain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H þ -ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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“…They were selected specifically because their mechanisms of action are wellcharacterised and their toxicity would be expected to be associated with ATase levels, if this enzyme controls sensitivity in these cells (Gibson et al, 1984;Stevens et al, 1984;Pegg, 1990).…”

mentioning

confidence: 99%

O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines

Walker

Masters²,

Margison³

1992

Br J Cancer

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Summary The DNA repair enzyme, 06-alkylguanine-DNA-alkyltransferase (ATase), is thought to be the principal mechanism controlling resistance to nitrosoureas and related alkylating agents. We compared the sensitivities of five human testis and five bladder tumour cell lines to two nitrosoureas (N-nitroso-Nmethylurea (MNU) and mitozolomide) with cellular levels of ATase. Enzyme levels ranged from 3 to 206 fmol mg-1 protein (0.1 x 104 to 5.1 x 104 molecules/cell) in the testis lines and from 11 to 603 fmol mg-1 (0.4 x 104 to 9.1 x 104 molecules/cell) in the bladder lines. Based on IC5Os in an MTT assay, the testis tumour cell lines were, on average, four times more sensitive to MNU and six times more sensitive to mitozolomide than the bladder cell lines. The cytotoxicities of MNU and mitozolomide were closely related (R = 0.9). In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78). In the bladder cell lines and overall, ATase activity correlated with cellular sensitivity to neither agent. Relatively high levels of resistance occurred in cells expressing low levels of ATase, and amongst cell lines expressing high levels of ATase, large differences in IC5Os were observed. These results support the suggestion that resistance to nitrosoureas can be mediated by mechanisms other than ATase and that at relatively high levels of expression, ATase does not confer resistance in proportion to its activity.Cells expressing ATase are commonly resistant to the cytotoxic effects of mono-and bifunctional methylating and chloroethylating agents (Pegg, 1990), including the chloroethylnitrosoureas (CNUs) used as chemotherapeutic drugs. ATase is thought to reduce the cytotoxicity of these agents by transferring the chloroethyl group from the o6 position of guanine to a cysteine residue in the active site of the enzyme before interstrand crosslinks can be formed (Kohn, 1977;Erickson et al., 1980a;1980b). Each enzyme molecule can remove only one alkyl group, as the reaction is autoinactivating (Pegg, 1990). This may be of clinical relevance as it has been suggested that tumours with low levels of this enzyme are more likely to respond to chemotherapy using nitrosoureas.There are three main lines of evidence indicating that ATase influences sensitivity to nitrosoureas. Firstly, cultured cells expressing low levels of the enzyme can be hypersensitive to nitrosoureas (Day et al., 1980;Bodell et al., 1986;Jelinek et al., 1988;Smith & Brent, 1989), though this is not always the case (Samson & Linn, 1987;Maynard et al., 1989). Secondly, pretreatment of cells with agents which deplete endogenous ATase, such as alkylating agents or 06_ methylguanine as free base, increases sensitivity to subsequent exposure to alkylating agents (Gibson et al., 1986;Gerson et al., 1988 The abbreviations used are: BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetra-acetic acid, disodium salt; IC50, drug concentration causing a 50% decrease in optical density com...

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Antitumour imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumor agent

Cited by 210 publications

References 6 publications

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines

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