WR-2721: enhanced chemoprotection by increasing cyclophosphamide activation with phenobarbitol

Journal Article · Mon Mar 01 04:00:00 EST 1982 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(82)90686-1· OSTI ID:6702372

Glover, D J; Yuhas, J M; Glick, J H

In the animal model, WR-2721 protects the bone marrow against the cytotoxicity of cyclophosphamide (CYC) and nitrogen mustard (HN/sub 2/) by factors of 1.5-2.4 and 3.2-4.6, respectively. NH/sub 2/ is rapidly metabolized within minutes, while CYC is activated slowly over hours by the hepatic mixed function oxidases. The prolonged half-life of CYC may account for the reduced chemoprotection as compared to NH/sub 2/. Phenobarbitol (PB) pretreatment significantly shortens the half-life of CYC in man and in the rat model. Thus, pretreatment with PB, by inducing hepatic microsomal enzymes, may enhance chemoprotection with WR-2721. Experiments were performed to determine: (1) The effect of PB pretreatment on the clearance of WR-2721; (2) Whether WR-2721 protects against CYC myelotoxicity measured by daily leukocyte counts; (3) Whether PB increases chemoprotection with WR-2721 and CYC. Female Fisher rats were pretreated with daily PB 40 mg/kg intraperitoneally (ip) for four days prior to the administration of 100 mg/kg CYC ip with and without WR-2721 200 mg/kg ip. Controls received saline ip in place of PB on the same schedule. CYC levels and alkylating activity were measured at 15, 13, 60 and 180 minutes after CYC. Serum and tissue levels of WR-2721 were assayed by radiolabel technique. Following CYC, daily WBC were obtained for 10 days at which point all counts had returned to baseline. PB may increase the acute toxicity of WR-2721 as judged by hypothermic response. PB had minimal effects on serum and tissue level of WR-2721. PB appears to enhance WR-2721's chemoprotection against myelosuppression from CYC by hastening marrow recovery and decreasing the extent of leukopenia.

• Research Organization: Univ. Pennsylvania, Philadelphia
• OSTI ID: 6702372
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 8:3/4; ISSN IOBPD
• Country of Publication: United States
• Language: English

Related Subjects

560305* -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKYLATING AGENTS
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AZINES
BARBITURATES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD COUNT
BODY FLUIDS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
CHEMICAL ACTIVATION
DISEASES
DRUGS
ENDOXAN
ENZYMES
HEMIC DISEASES
HETEROCYCLIC COMPOUNDS
HYPNOTICS AND SEDATIVES
IMMUNOSUPPRESSIVE DRUGS
LEUKOCYTES
LEUKOPENIA
MAMMALS
MATERIALS
MIXED-FUNCTION OXIDASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXIDOREDUCTASES
OXYGENASES
PHENOBARBITAL
PYRIMIDINES
RADIOPROTECTIVE SUBSTANCES
RATS
RODENTS
SYNERGISM
THIOIC ACIDS
VERTEBRATES