This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

LY186641 (diarylsulfonylurea, [DSU]) is a novel anticancer agent because of its unique diarylsulfonylurea chemical structure, broad-spectrum antisolid-tumor activity in preclinical models, presumed novel mechanism of action and preclinical toxicities of methemoglobinemia (Met Hgb) and decreased red blood cell (RBC) survival. In this study, the in vitro drug sensitivity of human tumors as well as clinical pharmacology and toxicology of DSU in patients with cancer were examined. DSU was administered orally, daily for 7 days with a 3-week treatment cycle. Dose-limiting toxicities were Met Hgb and RBC hemolysis. The maximum-tolerated dose was found to be 1,200 mg/m2/d for 7 days. In pharmacokinetic studies, DSU was found to have a prolonged serum half-life (approximately 30 hours) and a large area under the plasma disappearance curve (8,883.3 micrograms.hr/mL at 1,200 mg/m2/d). A partial remission was observed in one patient with refractory ovarian cancer. In conclusion, DSU can be safely administered to cancer patients and does display antitumor activity. Potential means of obviating the toxicities of this compound are discussed.

The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified.

The semi-synthetic vinca alkaloid vinzolidine was administered to advanced cancer patients as an intravenous bolus on a three day schedule every 21 days. Forty-two patients were treated in this phase I trial. Five partial remissions (breast-l, melanoma-2, renal cancer-2) were seen in 30 evaluable patients. The dose limiting toxicities were myelosuppression and neuropathy. Erratic myelosuppression from course to course within the same patient as seen in previous trials with oral vinzolidine, was not observed with the intravenous formulation. The measured pharmacokinetic parameters conformed best to a 2-compartment model with a mean terminal half-life of 23 hours. The anti-tumor activity observed during this phase I trial and acceptable toxicity provide the basis for initiating phase II studies in selected forms of cancer.

A 56-year-old patient with multiple myeloma experienced an extravasation of doxorubicin (DOX) and vincristine administered as a 96-hour infusion. An unknown quantity of solution (2.1 mg/ml of DOX and 0.1 mg/ml of vincristine) extravasated into the medial aspect of the right upper arm. This was caused by the axillary blockage of a 14-inch, 18-gauge catheter that had been inserted through the antecubital fossa. The only physical complaint mentioned by the patient was a dull muscle ache. No local swelling or redness was apparent until 2 weeks after the extravasation occurred, at which time surgical debridement yielded a 9.2 x 4 x 2-cm section of fascia and thrombosed vein with a normal-appearing margin. A high performance liquid chromatography analysis of different tissue areas in the surgical specimen yielded DOX levels of 1.25 to 7.94 micrograms/g of wet tissue weight. These levels are approximately tenfold higher than those of any previous extravasation reports. Slightly lower levels of the DOX aglycone (but no doxorubicinol) were recovered from these tissues. An important finding was the DOX level of 2.7 micrograms/g in the margin of the specimen, predicting a need for further surgery. Indeed, a second debridement was performed 1 week later, followed by a split thickness skin graft. Although the myeloma remains in clinical remission, use of the effected right arm is limited primarily by skin contracture at the graft site. This case demonstrates that high DOX levels can be deposited in soft tissues during prolonged DOX infusions without producing severe acute symptomatology. Furthermore, an analysis of DOX content in excised tissues may help guide the surgical management of the patient experiencing an extravasation.