A phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients.
OBJECTIVE
Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks.


METHODS
Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m(2)). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose.


RESULTS
Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m(2), but lower doses were well tolerated. No responses were seen, but 28% had stable disease for > or =3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m(2) indicated the following averages: maximum plasma level, 1.6 microM; area under the plasma concentration-time curve, 56 microM.h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at > or =281 mg/m(2)).


CONCLUSIONS
Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m(2), which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.
National Cancer Institute-Navy Hematology/Oncology, National Naval Medical Center, Bethesda, Maryland 20889, USA. gremj@mail.nih.gov
Jean L
JL
Grem
Nancy
N
Harold
Bruce
B
Keith
Alice P
AP
Chen
Viven
V
Kao
Chris H
CH
Takimoto
J Michael
JM
Hamilton
Janet
J
Pang
Marie
M
Pace
Gada B
GB
Jasser
Mary G
MG
Quinn
Brian P
BP
Monahan
D000166:Acridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017209:Apoptosis; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000166:Acridines; D000970:Antineoplastic Agents; D011720:Pyrazoles; C064541:NSC 366140