Phase II study of amonafide (Nafidamide, NSC 308847) in advanced colorectal cancer

Abstract

Amonafide, a benzisoquinoline-1,3-dione with anti-tumor activity in preclinical screens, was administered to patients with recurrent or metastatic bidimensionally measurable colorectal cancer. Fourteen patients with no prior chemotherapy for advanced disease, performance status 0-1, and normal bone marrow, renal, and hepatic function were entered. Amonafide 300 mg/m2 was administered intravenously over 1 hour daily for five consecutive days; courses were repeated every three weeks. The major side effect was neutropenia: Grade 3 or 4 toxicity occurred in 5/14 patients. Other toxicities included nausea and vomiting, flulike symptoms, fever, rash and alopecia. Three patients had stable disease, but there were no responses observed. Amonafide at this dose and schedule has no activity in the treatment of colorectal cancer.

2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a Novel Nonhematotoxic Naphthalimide Derivative with Potent Antitumor Activity

“…Four of the 10 mice receiving 20 mg/kg of 2 also died before the end of the experiment, and the remaining six mice displayed a marked decrease in their platelet numbers (Figure ). The present experiment, therefore, perfectly reproduced the known hematotoxicity of amonafide ( 1 ) and N -acetyl-amonafide ( 2 ). − Compounds 27 , 29 , and 33 also displayed significant ( p < 0.05 to p < 0.001) decreases in platelet numbers compared to controls (Figure ). In addition, 29 provoked severe decreases in RBC counts (data not shown).…”

“…Table 1 also reveals that amonafide (1) was associated with weak in vivo activity in the L1210 leukemia model (T/C ) 140%), while its toxic metabolite, N-acetyl-amonafide (2), displayed high activity. Of the 44 total naphthalimide derivatives evaluated in the course of the present study, four (17,27,29,33) were associated with marked in vivo activity (T/C values >300% or close to 300%) in the L1210 mouse leukemia model, with low in vivo toxicity (MTDs g80 mg/kg).…”

“…The present experiment, therefore, perfectly reproduced the known hematotoxicity of amonafide (1) and N-acetyl-amonafide (2). [17][18][19][20][21] Compounds 27, 29, and 33 also displayed significant (p < 0.05 to p < 0.001) decreases in platelet numbers compared to controls (Figure 3). In addition, 29 provoked severe decreases in RBC counts (data not shown).…”

“…The compound has, however, with the exception of advanced breast cancer, , shown no activity or only limited activity against a range of different cancer types. Dose-limiting myelosuppression is also a key issue for the compound. − The compound's toxicity, which is highly variable, is linked to its metabolism. Amonafide can be metabolized by N -oxidation (via CYP1A2) to generate a rapidly eliminated inactive metabolite.…”

“…Dose-limiting myelosuppression is also a key issue for the compound. [17][18][19][20][21] The compound's toxicity, which is highly variable, is linked to its metabolism. Amonafide can be metabolized by N-oxidation (via CYP1A2) to generate a rapidly eliminated inactive metabolite.…”