Circadian time dependence of murine tolerance for the alkylating agent peptichemio

Since the extent of host toxicity of cytostatics is considerably affected by dosing time, a chronopharmacologic approach was undertaken for optimizing the therapeutic index of the alkylating agent, peptichemio (PTC). In 4 studies involving a total of 463 male B6D2F1 mice, a highly statistically significant circadian rhythm characterized murine tolerance for PTC (8 or 10 mg/kg/day i.v. X 3 days). Six circadian stages were explored (3, 7, 11, 15, 19 and 23 Hours After Light Onset--HALO). Day-40 survival rate varied between 20% (PTC at 3 HALO) and 55% (PTC at 15 HALO) (chi 2 = 16.7; P less than 0.01). In each study, body weight loss was maximal in mice injected with PTC at 3 HALO and minimal in those treated at 15 HALO (P less than 0.01). In a further study involving 96 male B6D2F1 mice, the toxicity of PTC on several target tissues (bone marrow, spleen, small bowel, colon, liver, kidney and lungs) was investigated by histology and leukocyte count as a function of drug dosing time. A circadian rhythm in the susceptibility of the bone marrow, the spleen and the intestinal tract was demonstrated. Optimal murine tolerance for PTC resulted from dosing it at 15 HALO, e.g. in the first half of the activity span.