Pharmacokinetic evaluation of zeniplatin in humans.

Zeniplatin, a more water-soluble organoplatinum than cisplatin, was evaluated for clinical pharmacology in the context of a phase II trial in previously treated patients with ovarian carcinoma. A total of 12 patients were given zeniplatin at 120 mg/m2 by rapid intravenous infusion over 90 min, with both blood and urine being sampled. All platinum moieties were analyzed in whole blood, plasma, plasma ultrafiltrate, and urine by atomic absorption, and free zeniplatin was analyzed in plasma ultrafiltrate by specific high-performance liquid chromatography (HPLC). In a comparison of the platinum-time concentration curve, AUC (area under the curve) values indicated that approximately 90% of platinum moieties were bound to circulating plasma proteins. There was no evidence of drug accumulation after repetitive dosing. The terminal half-life (t1/2) of this drug in plasma ultrafiltrate (3.7-7.2 h.) as measured by HPLC was slightly longer than that of carboplatin, whereas total platinum moieties in plasma displayed a long t1/2 (124-154 h). Approximately 60% of platinum moieties could be recovered in the urine within 24 h. These findings suggest that zeniplatin has a pharmacokinetic profile similar to that of carboplatin.

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin.

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).

Phase II trial of zeniplatin (CL 286,558), a new patinum compound, in patients with advanced ovarian cancer previously treated with organoplatinum-based therapy.

There is a critical need to find new chemotherapeutic agents that are active in platinum-refractory ovarian cancer. A phase II trial of zeniplatin (CL 286,558), a third-generation platinum compound, was conducted in 31 patients with advanced ovarian cancer to examine the safety and activity of the agent when used as a salvage treatment in individuals previously exposed to organoplatinum-based therapy. In general the drug was well tolerated, with moderate emesis and bone marrow suppression being observed in most patients. An unexpected side-effect was significant fever, of unknown etiology, which was noted in 16% of patients. Out of 20 patients, 2 (10%; 95% confidence intervals: 1%-32%) with clinically defined platinum-refractory disease achieved a partial response. Unfortunately, although we have defined definite but modest activity for zeniplatin in platinum-refractory ovarian cancer, further development of this drug has been discontinued because of the severe renal toxicity observed in other clinical trials of this cytotoxic agent.

Different patterns of chromosome and molecular breakage in classic Ph1 chronic myelogenous leukemia (CML) and variant Ph1 CML.

Variant translocations involving either chromosome 9, chromosome 22, or both with other chromosomes have been reported in about 8% of chronic myelogenous leukemia (CML) patients. In the 22 Ph+ patients studied in our laboratory, two showed variant translocations: t(9;22;11) (q34;q11;q13), and t(9;11) (q34;q11). We compared the pattern of involvement of different chromosomes (and bands) in secondary structural changes in CMLs carrying the t(9;22) (q34;q11) and in the variant translocations. Analysis showed significant differences in the pattern of involvement of different chromosomes and chromosome sites in the secondary structural changes in classic CMLs. This study, thus identifies nonrandomly involved chromosome sites that may be targeted for detailed molecular analysis to obtain an understanding of their role in disease progression. In the variant translocations chromosomes and chromosome bands were nonrandomly involved. Breakpoint cluster region (bcr) of the BCR gene was found to be rearranged in our two cases. We compared the location of molecular breaks within the bcr in classic and variant translocations. We found that translocation breaks occurred more frequently in the 5' region, and less frequently in the 3' region of bcr in variant translocations as compared with classic translocations. The significance of these findings in the etiology of CML is discussed.

Catheter fracture and embolization in a totally implanted venous access catheter.

A totally implanted venous access system was placed in a 24-year-old male patient with Hodgkins disease for chemotherapy. Twelve months after implantation it was noted on chest x-ray that the catheter had fractured and the distal fragment embolized to the right ventricle. Catheter separation and embolization is a recognized but uncommon complication of Hickman catheters. It is an even rarer complication of implanted central venous catheters. With the increasing use of these new venous access systems this complication may become a more prevalent, but an avoidable complication.