title: Radiation enhancement by 9-aminocamptothecin: the effect of fractionation and timing of administration.
abstract: OBJECTIVE
  The camptothecins (CPTs) are potent radiation sensitizers in vivo but the optimal schedule of administration is unknown. In this article, the effects of irradiation combined with 9-aminocamptothecin (9AC) on a mouse mammary cancer and the gastrointestinal tract were compared for single and fractionated treatment. We also examined the circadian dependency for cytotoxicity, radiation sensitization, and acute toxicity after single doses of 9AC given at six different times over 24 h.
  
  
  METHODS
  9AC was administered intramuscularly to C3Hf/Kam mice with and without an 8 mm mouse mammary carcinoma (MCa-4). Acute toxicity was assessed by examination of body weight loss, peripheral blood counts, clinical assessment of diarrhea, and survival. Radiation sensitization was assessed using the tumor regrowth delay model.
  
  
  RESULTS
  Regrowth delay of MCa-4 tumor after a single treatment of 15 Gy is comparable to 28 Gy given in 14 fractions (absolute regrowth delays of 7.1 days and 6.6 days, respectively). With 9AC alone, comparable tumor regrowth was obtained with a total dose of 4 mg/kg given intramuscularly repeated twice weekly (1 mg/kg doses X 4), or as a single injection of 4 mg/kg (2.9 days and 3.8 days, respectively). 9-AC and irradiation together in single doses of 15 Gy and 4 mg/kg resulted in little radiation sensitization compared to the repeated 9AC schedule combined with fractionated irradiation [Dose Modifying Factors (DMF) of 1.12 vs. 2.8, respectively]. Acute normal tissue toxicity after single or fractionated 9AC treatment was assessed at six times over a 24-h period (6 A.M., 10 A.M., 2 P.M., 6 P.M., 10 P.M., and 2 A.M.) and was highest at 2 A.M. after either single or multiple doses. A single dose of 9AC administered with single fraction irradiation could be escalated by 33% when given at the best-tolerated time.
  
  
  CONCLUSIONS
  The frequency and timing of CPT administration with irradiation are important factors to be considered in the design of clinical protocols. CPTs are S-phase inhibitors that are better tolerated by the mouse when given during the rest phase when intestinal mucosal proliferation is relatively low. A modest increase in CPT dosage was possible by choosing the best tolerated time to administer the radiation sensitizer. This concept could potentially be evaluated in clinical trials with this class of agents.
authors.affiliation: Department of Radiation Oncology, University of Virginia Health System, Charlottesville 22903, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Kirichenko
authors.forename: T A
authors.initials: TA
authors.lastname: Rich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002940:Circadian Rhythm; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D007273:Injections, Intramuscular; D015674:Mammary Neoplasms, Animal / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000633:toxicity; D013047:Specific Pathogen-Free Organisms
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C080125:9-aminocamptothecin; D002166:Camptothecin