Cytotoxicity of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) on Mer+, Mer+Rem- and Mer- cell lines: differential potentiation by 3-acetamidobenzamide

Lunn, J M; Harris, Adrian L.

doi:10.1038/bjc.1988.8

Cited by 23 publications

(7 citation statements)

References 29 publications

(22 reference statements)

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“…Although the ability to form a monomethyl species is required for antitumour activity, this may not be the sole mechanism by which triazenes exert their in vivo antitumour activity (Gescher et al, 1981;Sava et al, 1988). Some Mer-cells are relatively sensitive to the monomethyl species of dacarbazine in vitro, but it is unclear whether this phenotype is a direct or indirect determinant of the lethal effects of triazenes (Gibson et al, 1986;Lunn & Harris, 1988). However, even if monomethyl metabolite formation is not the sole determinant of activity, a higher level might be expected to be associated with improved activity.…”

Section: Discussionmentioning

confidence: 99%

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277

Foster

Newell²,

Carmichael³

et al. 1993

Br J Cancer

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Summary Decarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. CBIO-277 is a phenyl dimethyltriazene which, like dacarbazine, requires metabolic activation to its corresponding monomethyl species for antitumour activity. In preclinical models (human melanoma xenografts and transplantable rodent tumours) CB10-277 showed a similar spectrum and level of activity when compared to dacarbazine. Pharmacokinetic studies were performed with CBIO-277 in mice treated i.v. at the LDIO (750 mg m-2) and plasma analysed by HPLC. The parent drug area under the plasma concentration vs time curve (AUC) was 142 mM x minutes). Drug metabolism occurred as evidenced by the HPLC identification of the monomethyl species (AUC = 8 mM x minutes) as well as other metabolites.A Phase I trial using a short infusion with doses repeated every 21 days has been performed. Thirty-six patients received 80 courses over a dose range of 80 -6,000 mg m-2. The dose limiting toxicity was nausea and vomiting which occurred in 80% of the evaluable courses > 900 mg m-2. The only other common side effect was a flushing or warm sensation, which occurred in over 75% of courses at > 1,350 mg m-2. There were no hemodynamic consequences. Responses occurred in patients with melanoma (one complete, two partial, one mixed/I 1), sarcoma (one mixed/6) and carcinoid (one partial/i). Pharmacokinetics were performed in 46 courses. The CB10-277 AUC increased linearly with dose (r = 0.9203, P <0.001) up to 700 mM x minutes at 6,000 mg m-2). Evidence of CBIO-277 metabolism was observed, as in mice, by detection of the monomethyl species and other metabolites. However, the plasma levels of the monomethyl species in patients (1.8 and 3.7 mM x minutes at 6,000 mg m-2) were less than those predicted from studies in mice. Despite this, antitumour activity in dacarbazine sensitive histologies was observed and additional studies with CB10-277 are recommended.

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Section: Discussionmentioning

confidence: 99%

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277

Foster

Newell²,

Carmichael³

et al. 1993

Br J Cancer

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“…In addition, to the best of our knowledge, we could not find any primary data that would support the statement that MTIC is not able to penetrate cell membranes effectively. Several in vitro studies have shown that MTIC treatment of a variety of tumor cells (HeLa cells, colon carcinoma or lung adenocarcinoma cells, murine lymphoma cells) reduced cell viability as efficiently as DTIC and TMZ and induced DNA double strand breaks [84,85,86]. In those experiments, MTIC was simply added to the cell culture, thus it is likely that it is able to cross cell membranes in order to induce those biological effects.…”

Section: Open Questions Regarding Tmz’s Mode Of Actionmentioning

confidence: 99%

Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

Strobel¹,

Baisch²,

Fitzel³

et al. 2019

Biomedicines

167

143

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The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.

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“…ATase is able to transfer the methyl group from the 06 position of guanine to an internal cysteine residue in an auto-inactivating stoichiometric reaction. Experimental models using ATase-deficient cell lines or xenografts show them to be more sensitive to DTIC than lines or xenografts with high activity (Hayward & Parsons, 1984;Gibson et al, 1986;Catapano et al, 1987;D'Incalci et al, 1988;Lunn & Harris, 1988;Foster et al, 1990). The strongest evidence for the cytotoxic effects of 06-alkylguanine in DNA comes from ATase cDNA transfection experiments which show that expression of prokaryotic or eukaryotic ATase cDNA in mammalian cells protects them against the toxic effects to these agents (Brennand & Margison, 1986;Kataoka et al, 1986;Samson et al, 1986;Kaina et al, 1991).…”

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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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Cytotoxicity of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) on Mer+, Mer+Rem- and Mer- cell lines: differential potentiation by 3-acetamidobenzamide

Cited by 23 publications

References 29 publications

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277

Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

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

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