In vivo metabolism and reaction with dna of the cytostatic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)

Meer, Lisa; Janzer, Robert C.; Kleihues, Paul; Kolar, G.F.

doi:10.1016/0006-2952(86)90419-3

Cited by 79 publications

(35 citation statements)

References 14 publications

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“…DTIC undergoes metabolic N-demethylation to give the cytotoxic monomethyl triazene, 5-(3-methyl-l-triazeno)imidazole-4-carboxamide (MTIC) which methylates DNA, producing among 12 other lesions, 06-methylguanine (Meer et al, 1986). There is increasing evidence to suggest that o6_ methylguanine is the principal cytotoxic event following DTIC and that 06-alkylguanine-DNA alkyltransferase (ATase) expression may be a major factor in cellular resistance to such agents (D'Incalci et al, 1988;Pegg, 1990).…”

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confidence: 99%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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Summary There is increasing experimental evidence to suggest that expression of 06-alkylguanine-DNAalkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the 06-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m') at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800mg m2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.

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Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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“…DTIC is a prodrug that requires metabolic activation to produce the methylating agent MTIC which can then react with DNA (Meer et al, 1986). The present study demonstrates the presence of 06-MedG in the DNA of peripheral leucocytes from patients receiving combined DTIC/fotemustine therapy and hence the ability of these patients to activate DTIC.…”

Section: Discussionmentioning

confidence: 52%

“…It undergoes metabolic N-demethylation to give the monomethyl triazene, 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), which methylates cellular macromolecules including DNA. Among the 12 DNA lesions so formed, 06-methyldeoxyguanosine (06-MedG) is thought to be the principal cytotoxic product (Meer et al, 1986). It has been shown that resistance to MTIC and related agents involves the activity of the DNA repair protein 06-alkylguanine-DNA alkyltransferase (ATase), which transfers the methyl group from 06-MedG to an internal cysteine residue in an autoinactivating, stoichiometric reaction (Hayward & Parsons, 1984;Gibson et al, 1986;Catapano et al, 1987;D'Incalci et al, 1988;Lunn & Harris, 1988;Foster et al, 1990).…”

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confidence: 99%

Formation and loss of O6-methyldeoxyguanosine in human leucocyte DNA following sequential DTIC and fotemustine chemotherapy

Lee

Margison²,

Thatcher³

et al. 1994

Br J Cancer

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There is increasing evidence to indicate that O6-methyldeoxyguanosine (O6-MedG) formation in DNA is a critical cytotoxic event following exposure to certain anti-tumour alkylating agents and that the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) can confer resistance to these agents. We recently demonstrated a wide inter-individual variation in the depletion and subsequent regeneration of ATase in human peripheral blood lymphocytes following sequential DTIC (400 mg m-2) and fotemustine (100 mg m-2) treatment, with the nadir ATase activity occurring approximately 4 h after DTIC administration. We have now measured the formation and loss of O6-methyldeoxyguanosine (O6-MedG) in the DNA of peripheral leucocytes of eight patients receiving this treatment regimen. O6-MedG could be detected within 1 h and maximal levels occurred approximately 3-5 h after DTIC administration. Following the first treatment cycle, considerable inter-individual variation was observed in the peak O6-MedG levels, with values ranging from 0.71 to 14.3 mumol of O6-MedG per mol of dG (6.41 +/- 5.53, mean +/- s.d.). Inter- and intra-individual variation in the extent of O6-MedG formation was also seen in patients receiving additional treatment cycles. This may be a consequence of inter-patient differences in the capacity for metabolism of DTIC to release a methylating intermediate and could be one of the determinants of clinical response. Both the pretreatment ATase levels and the extent of ATase depletion were inversely correlated with the amount of O6-MedG formed in leucocyte DNA when expressed either as peak levels (r = -0.59 and -0.75 respectively) or as the area under the concentration-time curve (r = -0.72 and -0.73 respectively). One complete and one partial clinical response were seen, and these occurred in the two patients with the highest O6-MedG levels in the peripheral leucocyte DNA, although the true significance of this observation has yet to be established.

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“…Alkylating agents, such as dacarbazine (DTIC), used to treat malignant melanoma, lymphoma and soft tissue sarcoma, and temozolomide (TMZ), used to treat brain cancers and tumors that have metastasized to the brain, act mainly via S N 2 reactions to methylate the N7 and O6 of guanine and N3 of adenine [15,16]. Bifunctional alkylating agents can cause DNA crosslinks.…”

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confidence: 99%

Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors

Bernstein¹,

Karimi‐Busheri²,

Rasouli-Nia³

et al. 2008

ACAMC

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The cytotoxicity of many antineoplastic agents is due to their capacity to damage DNA and there is evidence indicating that DNA repair contributes to the cellular resistance to such agents. DNA strand breaks constitute a significant proportion of the lesions generated by a broad range of genotoxic agents, either directly, or during the course of DNA repair. Strand breaks that are caused by many agents including ionizing radiation, topoisomerase I inhibitors, and DNA repair glycosylases such as NEIL1 and NEIL2, often contain 5'-hydroxyl and/or 3'-phosphate termini. These ends must be converted to 5'-phosphate and 3'-hydroxyl termini in order to allow DNA polymerases and ligases to catalyze repair synthesis and strand rejoining. A key enzyme involved in this end-processing is polynucleotide kinase (PNK), which possesses two enzyme activities, a DNA 5'-kinase activity and a 3'-phosphatase activity. PNK participates in the single-strand break repair pathway and the nonhomologous end joining pathway for double-strand break repair. RNAi-mediated down-regulation of PNK renders cells more sensitive to ionizing radiation and camptothecin, a topoisomerase I inhibitor. Structural analysis of PNK revealed the protein is composed of three domains, the kinase domain at the C-terminus, the phosphatase domain in the centre and a forkhead associated (FHA) domain at the N-terminus. The FHA domain plays a critical role in the binding of PNK to other DNA repair proteins. Thus each PNK domain may be a suitable target for small molecule inhibition to effectively reduce resistance to ionizing radiation and topoisomerase I inhibitors. KeywordsDNA damage; DNA repair; small molecule inhibitors; polynucleotide kinase; FHA; kinase; phosphatase Cancer therapy and DNA damage and repairCancer continues to be a major health problem. This year (2007) it is estimated that approximately 1.6 million individuals will be diagnosed with cancer in the USA and Canada (excluding basal and squamous cell skin cancer) and that approximately 630,000 will die from cancer (American Cancer Society and Canadian Cancer Society). Despite major advances in targeted chemotherapy, the major forms of therapy continue to be surgery, radiotherapy and conventional chemotherapy. The cellular target for radiotherapy and many conventional drugs Corresponding authors: Michael Weinfeld, Experimental Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta T6G 1Z2, Canada, michaelw@cancerboard.ab.ca, Tel: (780) 432 8438, Mark Glover, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada, mark.glover@ualberta.ca, Tel: (780) 492-2136. NIH Public Access Author ManuscriptAnticancer Agents Med Chem. Author manuscript; available in PMC 2010 October 22. Published in final edited form as:Anticancer Agents Med Chem. 2008 May ; 8(4): 358-367. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptis the DNA within the nuclei (and possibly mitochondria). Consequently, the levels of induced DNA damage and t...

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In vivo metabolism and reaction with dna of the cytostatic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)

Cited by 79 publications

References 14 publications

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Formation and loss of O6-methyldeoxyguanosine in human leucocyte DNA following sequential DTIC and fotemustine chemotherapy

Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors

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