Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation.

PURPOSE: Tirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues. METHODS AND MATERIALS: Tirapazamine 9 mg/m2 to 21 mg/m2 was given i.v. 1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 i.v. after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment. RESULTS: Subjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping. CONCLUSION: Muscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing.

Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells.

Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) catalyzes the rate-limiting reaction in the catabolism of endogenous uracil and thymine and exogenous fluoropyrimidines. DPD activity was studied in human blood mononuclear cell supernatants utilizing a new and sensitive radiochromatographic assay. Total DPD activity showed a linear correlation with supernatant protein concentration. The affinity constants (Km) for NADPH and thymine were approximately 10 and 1 mumol/l, respectively. Maximal activity (Vmax) was observed at 0.25 mmol/l NADPH and 10 mumol/l thymine, respectively. DPD activity in normal individuals was 8.0 +/- (SD) 2.2 nmol/mg protein/h, and ranged from 4.4 to 12.3 nmol/mg/h (n = 25). This activity range was quite similar to values obtained in patients with metastatic solid tumors treated with fluorodeoxyuridine (FUdR; n = 33, p = 0.57). No correlation was found to exist between mononuclear leucocyte DPD activity and the observed toxicity of FUdR in the tested patients. A bimodal distribution of DPD activity was observed in the patients and in normal individuals. The entire study population tested could be divided into two groups with respect to DPD activity; one group with high (greater than 8 nmol/mg/h) activity and another with low (less than 8 nmol/mg/h) activity. The possibility that sex differences may have been responsible for this distribution of DPD activity could not be excluded. The findings of this study are relevant to the pharmacogenetics of fluoropyrimidines in humans.

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.

Circadian pattern of continuous FUDR infusion reduces toxicities.

The toxicity and efficacy of at least a dozen of the most commonly used anticancer drugs vary predictably depending on when in the day they are given. In a series of murine experiments involving CD2F1 mice, we have demonstrated that the safest time for FUDR administration is the mid- to late activity span. In a clinical pilot study, an implantable programmable drug-administration device (Medtronic, Inc), allowing automatic dose modifications of continuous long-term infusion, was employed to investigate whether this is also true in cancer patients. Toxicity of FUDR given as continuous flat infusion was significantly greater than that of time-modified infusion regardless of the route of drug administration. Responses have occurred with at least equal frequency, and patients are currently being followed to see if the pattern of drug delivery has an effect on patient survival.

Cisplatin chronotherapy and disulfiram rescue reduce toxicity without interfering with anticancer activity: animal findings and preliminary clinical experiences.

Cisplatin-induced mortality and nephrotoxicity are each predictably worse when the drug is given at certain points within the circadian schedule. Oral disulfiram protects rats from toxic effects at some circadian stages but not others. This manuever does not diminish the anticancer activity of cisplatin in these rats. Human beings given 2 g of oral disulfiram and high doses of cisplatin at the circadian stage associated with least cisplatin nephrotoxicity (prospectively determined potassium excretion acrophase) suffer little or no kidney damage. Disulfiram administration apparently does not interfere with the antineoplastic activity of cisplatin in humans. This is the first demonstration of the feasibility of assignment of treatment time according to a measure of the patient's 'internal clock' as assessed by pretreatment marker rhythmometry. It also establishes the feasibility of giving disulfiram to human beings.

Advanced transitional cell bladder cancer: a treatable disease.

Although metastatic bladder cancer is difficult to treat effectively, chemotherapy combinations and schedules have emerged recently that can result in long-lasting complete responses in some patients. Response rates, response durations, and survival patterns of the entire patient population are, however, unsatisfactory. Whereas survival times of these patients following therapy with cisplatin alone or in combination with other drugs are not significantly different, complete response rates are higher and disease-free survival is longer when combinations are used. Higher dosages are associated with better response rates but also with substantial toxicity. Extensive local pretreatment or prior systemic chemotherapy reduces the likelihood of clinically meaningful disease response. Several adjuvant studies have demonstrated an advantage in length of disease-free survival for chemotherapy-treated patients when compared to those who are observed following operation. Metastatic transitional cell bladder cancer is a chemotherapeutically treatable malignancy. Locally advanced disease may be most effectively treated by aggressive surgery followed by cisplatin-based combination chemotherapy. The highest response rates and longest disease-free survivals are uniformly associated with aggressive and prolonged multidrug therapy.

Lack of antiemetic effect of high-dose metoclopramide.

Sixteen of 26 patients given 51 courses of treatment of the doxorubicin and cisplatin combination with no antiemetic therapy suffered the same number of vomiting episodes and had the same duration of vomiting as did the remaining ten patients given 20 cycles of this chemotherapy plus the standard high-dose metoclopramide regimen. This antiemetic regimen caused significant side effects in one fifth of the patients receiving it.