Treatment schedule dependency of antitumor effect of deoxyspergualin.
The effect of treatment schedule on antitumor activity of 15-deoxyspergualin (NKT-01) against P388 leukemia was studied by changing each 2 out of 3 factors of administration schedule (number of injections, injection interval, and injection period) with the rest being constant. The antitumor activity of NKT-01 was shown to be strongly time-dependent; higher efficacy was obtained with prolongation of treatment period and with increasing the number of injections. The dosing interval seemed not to be a dominant factor regarding the activity of NKT-01. The strong dependency on treatment period was also observed in continuous infusion schedules by using Alzet 2001 osmotic minipump. The degree of dependency on infusion period was estimated to be 3- to 4-fold stronger than that on the infused dose by logarithmical plotting of the infusion periods and infused daily doses required to produce 130% of T/C(%). The effective dose range by the continuous infusion was slightly narrower than that by the repeated bolus injections, although slightly higher maximal activity was obtained at the optimal dose. Hyperacute pharmacological toxicity caused by bolus injection of high dose (51.2 mg/kg) of NKT-01 did not occur by continuous infusion method even at much higher dose (409.6 mg/kg/day). Cumulative gastrointestinal toxicity was observed by prolonged continuous infusion as well as repetitive treatment schedule. From these results on antitumor activity and toxicity by various treatment schedules, recommendable clinical modality for NKT-01 seems to be the short-time infusion on every or every other day continuing for a few weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishikawa
K
K
Research Laboratories, Pharmaceuticals Group, Nippon Kayaku Co., Ltd.
Shibasaki
C
C
Takahashi
K
K
Takeuchi
T
T
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D004334:Drug Administration Schedule; D005260:Female; D006146:Guanidines / Q000008:administration & dosage* / Q000494:pharmacology; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains
D000903:Antibiotics, Antineoplastic; D006146:Guanidines; C037258:gusperimus