Circadian rhythm and seasonal dependence in the toxicological response of mice to epirubicin.

Compared to doxorubicin, equimolar epirubicin toxicity is reduced by about 50% by the epimerization of a hydrogen and hydroxyl group at the 4' position of the anthracycline sugar moiety. The circadian timing of doxorubicin administration markedly affects its lethal and sub-lethal bone marrow and gut toxicities in mice, as well as the severity of its clinical toxicity. We tested whether the timing of administration of equitoxic epirubicin doses similarly affected the toxicological response in female CD2F1 mice. A large and highly reproducible effect of the circadian stage of administration was documented with best drug tolerance occurring during the first half of the daily rest (light) span of the animals. In addition to this circadian rhythm, a significant seasonal effect was found with significantly fewer deaths occurring after epirubicin was given in the Summer, as compared to the Winter. Safest circadian timing for epirubicin is statistically significantly earlier in the day than for doxorubicin, while their seasonal patterns are quite similar.

Methylene blue protects intestinal mucosa from free radical-mediated sublethal radiation damage.

Susceptibility of the intestine to radiation damage is a primary reason for the failure of external beam radiation to cure intra-abdominal cancer. High-dose irradiation causes intestinal denudation, fluid loss, and resultant shock. Simple and effective methods for protecting the intestine from irradiation damage are not available. Many biological effects of ionizing irradiation are caused by free radical intermediates. We have previously reported that many of the toxicities of doxorubicin, a classic free radical generating anticancer agent, are blocked by methylene blue pretreatment. We have now found that pretreatment with methylene blue protects rats from intestinal damage, as measured histologically and by quantitative stool blood determinations. Whereas the exact mechanisms of this protection remain elusive, we believe this method of modulating the therapeutic index of ionizing radiation deserves additional preclinical and clinical study.

High-dose intensity, circadian-timed doxorubicin and cisplatin adjuvant chemotherapy for bladder cancer.

Thirteen patients with transitional cell carcinoma of the bladder received monthly circadian-timed doxorubicin and cisplatin chemotherapy immediately after radical cystectomy. In five patients cancer had spread through the serosa of the bladder wall and/or into the perivesical fat (stage C). In eight patients cancer had spread to other pelvic tissues and pelvic lymph nodes (stage D1). Ten of these 13 patients showed no recurrence of disease after a median follow-up period of 3.5 years (range, 1 to greater than 5.5); these patients received no chemotherapy for a median duration of 3 years (range, 2-5). Two of the three patients who ultimately failed had local tumor recurrence which occurred much later than is the usual case (40 and 52 months). This circadian-timed two-drug regimen, given in full doses for nine courses as adjuvant treatment, delays and may prevent local and distant recurrence of stage C and D1 bladder cancer.

High-dose intensity systemic therapy of metastatic bladder cancer.

Forty-three consecutively diagnosed patients with widely metastatic transitional cell carcinoma of the bladder (TCCB) were treated with a high-dose intensity, chronobiologically timed combination of doxorubicin and cisplatin, followed by Cytoxan (Mead Johnson Pharmaceuticals, Evansville, IN), 5-fluorouracil (5-FU), and cisplatin maintenance for up to 2 years. Fifty-seven percent of the 35 evaluable patients with widespread metastatic cancer responded objectively. Twenty-three percent had complete disappearance of all cancer. Median survival from first treatment for complete responders (CRs) was more than 2 years, and 1 year for partial responders (PRs). Three of the CRs were alive without evidence of cancer more than 2 years after stopping all therapy. High-dose intensity combination chemotherapy can induce durable CRs of widespread bladder cancer.

Lethal nephrotoxicity and hematologic toxicity of cis-diamminedichloroplatinum ameliorated by optimal circadian timing and hydration.

Three hundred and forty-one female F344 (Fischer) rats were kept in light for 8 hr alternating with darkness for 16 hr; some were observed for survival for 21 days, while others were killed for blood sampling 4.5 days after a single intraperitoneal (i.p.) injection of 11 mg/kg cis-diamminedichloroplatinum (cis-DDP). cis-DDP was administered with or without concomitant i.p. saline load at one of six equispaced circadian stages. This high dose of cis-DDP resulted in marked lethal and renal toxicity, but in a moderate bone marrow suppression. Blood urea nitrogen (BUN), circulating total white blood cell counts (WBC) and survival times revealed statistically significant circadian rhythms of drug toxicity (P less than 0.03). Optimal tolerance for cis-DDP gauged by these three variables resulted from drug administration in the second half of the dark span. Renal tolerance for cis-DDP guaged by BUN was improved two-fold by appropriate drug timing. This benefit from drug timing alone was further improved two-fold if hydration and cis-DDP were given at the optimal circadian stage. Hydration-induced ameloriation of cis-DDP nephrotoxicity requires time qualification of both hydration and cis-DDP.