PHASE-I AND PHARMACOLOGICAL STUDY OF THE PULMONARY CYTOTOXIN 4-IPOMEANOL ON A SINGLE DOSE SCHEDULE IN LUNG-CANCER PATIENTS - HEPATOTOXICITYIS DOSE LIMITING IN HUMANS

4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemica l-biological rationale as an antineoplastic agent targeted specificall y against lung cancer. This rationale is based on preclinical observat ions that metabolic activation and intracellular binding of IPO, as we ll as cytotoxicity, occurred selectively in tissues and cancers derive d from tissues that are rich in specific P450 mixed function oxidase e nzymes. Although tissues capable of activating IPO to cytotoxic interm ediates in vitro include liver, lung, and kidney, IPO has been demonst rated in rodents and dogs to undergo in situ activation, bind covalent ly, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening m odels, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale f or clinical development. Somewhat unexpectantly, hepatocellular toxici ty was the dose-limiting principal toxicity of IPO administered as a 3 0-min infusion every 3 weeks to patients with lung cancer. In this stu dy, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominately alanine aminotransferase, occur red in the majority of courses of IPO at 1032 mg/m2, which is the reco mmended IPO dose for subsequent phase II trials. At higher doses, hepa tocellular toxicity was more severe and was often associated with righ t upper quadrant pain and severe malaise. Toxic effects were also note d in other tissues capable of activating IPO, including possible nephr otoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two -compartment first order elimination model, the relationship between I PO dose and area under the disposition curve was curvilinear, suggesti ng saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (lambda1 and lambda2) were 6.7 and 114.5 min, respecti vely. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antit umor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients. The preponderance of clinical toxicity observed in liver rather than lung suggests that IPO may be preferentially activated and bound in liver rather than lung or other tissues in humans or that human lung tissue is more effective at detox ifying and/or is more tolerant to activated IPO than other species. In any event, these observations suggest further that the rationale for the clinical evaluation or ipo should be extended to include liver can cers and possibly renal cancers, as well as lung cancers.