Disease relevance of Ci-921

• CI-921s prolonged t1/2 in the dog and the dog's increased susceptibility to CI-921 toxicity suggested a relationship between MTD and t1/2 (h) [1].
• In studies conducted by Baguley and co-workers, CI-921 demonstrated activity against Lewis lung carcinoma in vivo, producing marked increases in life span and a high proportion of 60-day survivors [2].
• Potentiation of CI-921 activity was also found with the human tumour lines HT29 (colon), SW620 (colon) and FME (melanoma) [3].
• Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer [4].
• Like 9-aminoacridine and amsacrine, CI-921 is mutagenic to the Salmonella typhimurium frameshift tester strain TA1537, but shows no sign of inducing base pair changes in strain TA100 [5].

High impact information on Ci-921

• The P/DACT cell line, which shows the characteristics of a transport-mediated multidrug-resistant cell line, was cross-resistant to vincristine, doxorubicin, etoposide, and a number of acridine-substituted amsacrine derivatives, but was sensitive in vitro and in vivo to amsacrine and its analog CI-921 [6].
• CI-921 was developed to clinical trial largely on the basis of a series of studies at five cancer research laboratories that demonstrated its improved spectrum and degree of activity relative to those of amsacrine against murine tumor models [7].
• Pharmacokinetic, plasma protein binding, and toxicity data were available for CI-921 in mice, rats, rabbits, dogs, and humans [1].
• In order to determine whether CI-921 possesses any advantages over amsacrine in terms of tissue delivery, the pharmacokinetics of amsacrine and CI-921 were determined following i.v. injection in male B6D2F1 mice [8].
• The dog was a noticeable outlier in the relationship between the log maximum tolerated dose (MTD) (mg/kg) of CI-921 and log W [1].

Chemical compound and disease context of Ci-921

• Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, in mice, rats, rabbits, dogs, and humans [1].

Biological context of Ci-921

• Pharmacokinetics were evaluated following 65 infusions on Days 1 and 3 with plasma concentrations of CI-921 measured by high performance liquid chromatography [9].
• Pulse exposure of cells to CI-921 resulted in transient accumulations of cells in S and/or G2 phase depending upon dose [10].
• It was concluded that allometric equations may be developed for CI-921 and amsacrine from animal pharmacokinetic data which allow a reasonable prediction of Cl and Vss in patients, despite these agents being eliminated mainly by biotransformation [1].
• Cell viability was unaffected in Friend erythroleukemic cell cultures at concentrations up to 50 nM, although growth was inhibited by 50% following 24 h of continuous exposure to 9.5 nM or a 1 h pulse of 67.5 nM CI-921 [10].
• A study of amsalog (CI-921) administered orally on a 5-day schedule, with bioavailability and pharmacokinetically guided dose escalation [11].

Anatomical context of Ci-921

• The selectivity of CI-921 for L1210 versus bone marrow, and for LLAK versus L1210 or P388, was greater than that of amsacrine, again in keeping with its in vivo properties [12].
• Both amsacrine and its analogue, N-5-dimethyl-9-[(2-methoxy-4- methylsulphonylamino)phenylamino]-4-acridinecarboxamide (CI-921) are absorbed from the gastrointestinal tract in rabbits [13].

Associations of Ci-921 with other chemical compounds

• Both amsacrine and CI-921 inhibited production of hypochlorous acid by myeloperoxidase [14].
• Dose-dependent pharmacokinetics of N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]- 4-acridinecarboxamide (CI-921) in rabbits [15].

Gene context of Ci-921

• For CI-921 the allometric equations for the kinetic parameters calculated from plasma "free" concentrations were: Vssfu (liters) = 247W0.93 (r = 0.984, P = 0.002) and Clu (liters/h) = 186W0.76 (r = 0.961, P = 0.009) [1].
• The activity of DACA was comparable with that of 5-fluorouracil and superior to that of doxorubicin, cyclophosphamide and the experimental amsacrine analogue CI-921 [16].
• RESULTS: Patients who had a high TP level in normal liver tissue had significantly earlier recurrence (median disease-free survival, 819 days; 95% confidence interval [95% CI], 478-1044 days) compared with patients who had a low TP level (median disease-free survival, 1376 days; lower limit of 95% CI, 921 days; P = 0.0171) [17].

Analytical, diagnostic and therapeutic context of Ci-921

• CI-921 concentrations were measured by an HPLC method [18].
• A phase I trial of amsalog (CI-921) administered by intravenous infusion using a 5-day schedule [19].
• N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4- acridinecarboxamide (CI-921), which is an analogue of amsacrine, has entered phase I clinical trials as an antitumour drug [15].

References