Therapeutic manipulation of cytokines: transforming growth factor beta-1 protects mice treated with lethal doses of cytarabine.
We have developed a mouse model to utilize the specific regulatory effects of Transforming Growth Factor Beta-1 (TGF beta 1), the prototype for a family of growth inhibitory cytokines. A vital factor in the regulation of normal cellular growth for many cell types, TGF beta 1 prevents proliferation by reversibly arresting cells at the G1/S border of the cell cycle, thus delaying DNA synthesis and cell division. Since the dose of cytotoxic chemotherapy is limited by its adverse effects on bone marrow and gut cells, we proposed that a TGF beta 1-induced block at G1/S would diminish the S phase toxicity of high dose cytarabine (ara-C). The dosage of ara-C required to kill 90 per cent of 4-week old DBA/2 males was determined to be 3200 mg/kg every 12 hours x 2. Pretreatment with TGF beta 1 6-24 hours before the first dose of ara-C proved to be significantly protective; 8/9 TGF beta 1-pretreated mice survived versus 1/9 treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 10.89 P = 0.001). A second experiment confirmed this effect; TGF beta 1 pretreatment for 6-24 hours protected 9/9 versus 0/9 survivors in the group treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 18.0, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Pierce
D F
DF
Dept. of Surgery, Vanderbilt School of Medicine, Nashville, TN 37232-2730.
Coffey
R J
RJ
D000818:Animals; D003561:Cytarabine / Q000008:administration & dosage / Q000633:toxicity*; D004064:Digestive System / Q000166:cytology / Q000187:drug effects; D004334:Drug Administration Schedule; D004906:Erythrocyte Count / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D007958:Leukocyte Count / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009503:Neutropenia / Q000139:chemically induced / Q000503:physiopathology; D010976:Platelet Count / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D003561:Cytarabine