Studies on the mechanism of action of the tumour inhibitory triazenes

Audette, R. C. S.; Connors, T. A.; Mandel, H. George; Merai, Kanti; Ross, W. C. J.

doi:10.1016/0006-2952(73)90045-2

Cited by 88 publications

(17 citation statements)

References 18 publications

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“…It requires metabolic activation with formation of a monomethyl triazene for anti-tumour activity (Audette et al, 1973;Gescher et al, 1981). 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).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous compounds with structural similarities to dacarbazine that have preclinical activity exist (Loo & Lin, 1972;Audette et al, 1973;Connors et al, 1976;Loo et al, 1976;Giraldi et al, 1977;Hatheway et al, 1978;Wilman & Goddard, 1980;Gescher et al, 1981;Shealy & Krauth, 1966;Vaughn et al, 1984). CB10-277, a phenyl dimethyltriazene, is soluble and stable in aqueous solutions at physiologic pH (Wilman & Goddard, 1980).…”

Section: Discussionmentioning

confidence: 99%

“…Rodent tumours The rodent tumour models described in Table I were used (Audette et al, 1973;Potter & Robertson, 1960;Rosenoer et al, 1966 Weekly follow-up with physical examination, blood or serum studies to evaluate for possible bone marrow, renal and hepatic toxicity were performed. Repeat of previously positive radiological studies were performed every 6-9 weeks or sooner when indicated.…”

Section: Drugsmentioning

confidence: 99%

“…The basic triazene structure is shown in Figure 1. Compounds with different R, substitutents in position at N' (Loo & Lin, 1972;Audette et al, 1973;Connors et al, 1976;Loo et al, 1976;Giraldi et al, 1977;Hatheway et al, 1978;Wilman & Coddard, 1980;Gescher et al, 1981) and R2 and R3 substituents at N3 (Audette et al, 1973;Connors et al, 1976;Hatheway et al, 1978;Wilman & Goddard, 1980;Gescher et al, 1981;Shealy & Krauth, 1966;Vaughn et al, 1984) have been studied by various groups for activity in animal tumours. While a range of structural variations at RI can be tolerated, it is generally accepted that at least one methyl group is required at either R2 or R3 in order to allow the formation of a monomethyl species for antitumour activity (Audette et al, 1973).…”

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confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Drugsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…Little is known so far about the mechanism by which alkylating compounds, such as DTIC (Audette et al, 1973), have such a strong effect on the immunogenicity of tumour cells. Since DTIC treatment has to be protracted to obtain tumour lines rejected by a syngeneic host, it is quite likely that more than one mutational event occurs, but probably only a few of these lead to increased antigenicity.…”

Section: Animalsmentioning

confidence: 99%

DTIC xenogenized lines obtained from an L1210 clone: Clonal analysis of cytotoxic T lymphocyte reactivity

Marelli

Franco²,

Canti³

et al. 1988

Br J Cancer

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Antineoplastic compounds can induce on tumour cells new antigens that undetectable on parental cells and which are transmissible as a genetic character. In this study mouse leukaemia L1210 was cloned in vitro by limiting dilution and one cloned line was recloned in vivo. Four subcloned tumour cell lines (A,D,R,S) were xenogenized in vivo by DTIC treatment (A/DTIC, D/DTIC, R/DTIC, S/DTIC) following a schedule previously described. Up to 10(7) cells of these xenogenized subclones, injected i.p., were rejected by syngeneic hosts, although they grew in immunosuppressed hosts. The DTIC treated subclones were lysed by in vivo-primed, in vitro-restimulated (with the relevant subclone) lymphocytes. The cytotoxic lymphocyte activity was not strictly specific since parental, DTIC-untreated cells were also lysed, although less efficiently. CTL directed against the D/DTIC subclone were cloned by limiting dilution. Ninety-four CTL clones were assayed against L1210 subcloned cells, DTIC-treated and untreated, and against different murine tumours (syngeneic or allogenic). Three specific antigens could be identified in the 51Cr release assay. The DTIC subclones expressed one antigen that was specifically recognized by a set of CTL clones. A number of CTL clones were able to lyse the L1210 subcloned cell exclusively, targetting a tumour-associated antigen that did not appear to be modified in the DTIC-treated subclones. A third antigen was demonstrated in the parental and DTIC treated D subclone. On the basis of these results it was postulated that there was at least one common DTIC-inducible antigen specific and reproducible within an identical cell population. Moreover, DTIC treatment did not modify histocompatibility antigens or TAA pre-existing in L1210 cells. The findings discussed here provide new information about permanent xenogenization of tumour cells, which might be exploited for experimental chemo-immunotherapy of cancer.

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3-Methyl-1-p-tolyltriazene

White

Darbeau

2001

Encyclopedia of Reagents for Organic Synthesis

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Studies on the mechanism of action of the tumour inhibitory triazenes

Cited by 88 publications

References 18 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

DTIC xenogenized lines obtained from an L1210 clone: Clonal analysis of cytotoxic T lymphocyte reactivity

3-Methyl-1-p-tolyltriazene

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