Cisplatin (Platinol) and fluorouracil (5-FU) represent two broad-spectrum, high-efficacy antineoplastic agents. As such, they are widely used in solid tumor oncology. In combination regimens, cisplatin and 5-FU are active against refractory head and neck, lung, and gastric cancers and against squamous cell skin carcinomas. Preclinical models confirming a synergism between coadministered cisplatin and 5-FU support this broad clinical efficacy. In a human squamous cell carcinoma cell line (HST-1) model, Esaki et al demonstrated synergistic cytotoxicity when 5-FU was administered 24 hours before cisplatin. The same investigators subsequently showed that 5-FU pretreatment enhances cisplatin cytotoxicity even in cell lines previously selected for cisplatin resistance. In vivo HST-1 xenograft and primary murine colon tumor models have also substantiated the 5-FU/cisplatin sequence-dependent synergism.[3,4]
At least three different mechanisms of 5-FU/cisplatin synergism have been suggested in these preclinical investigations. Esaki et al suggested that cisplatin resistance is linked to cellular glutathione levels, noting increased intracellular levels in resistance-selected lines. Glutathione levels were markedly reduced in 5-FUpretreated cells, which were then highly susceptible to cisplatin. 5-FU is known to modulate the repair of platinumDNA adducts. 5-FU misincorporation into nuclear RNA may subsequently impair transcription of ERCC1, a nuclear enzyme critical to excisional repair of cisplatin-DNA adduct damage. Using an ovarian cell line model, Scanlon et al observed that cisplatin administered before 5-FU produced synergistic cytotoxicity. In this sequence, cisplatin notably increased intracellular reduced folate, thus enhancing 5-fluoro-2'-deoxyuridylatedeoxythymidine monophosphate (FdUMP-dTMP) synthase binding and 5-FU cytotoxicity.
Cisplatin and 5-FU therefore represent an efficacious combination regimen, based on both preclinical synergy and durable responses in various clinical studies. UFT and bis-aceto-ammine-dichloro-cyclohexyl-amine-platinum (IV) (JM-216) represent novel oral analogues of 5-FU and cisplatin, respectively. As discussed below, preclinical and phase I/II data for both single-agent UFT and JM-216 suggest efficacy, acceptable toxicity, and convenient administration. We therefore propose a phase I study of concomitantly administered UFT and JM-216.
UFT is a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil, complexed in a 1:4 molar ratio. Fujii et al noted that coadministration of uracil with tegafur significantly increased intratumoral levels of 5-FU. UFT is a prodrug, metabolized to the 5-FU by both hepatic cytochrome P-450 and the target tissues themselves.
Anttila et al examined the pharmacokinetics of tegafur after both oral and intravenous administration. Following an oral dose, distribution and elimination half-lives of 0.7 and 9.2 hours, respectively, were observed. The volume of distribution was essentially that of body water. Excellent oral bioavailability was observed, with an oral/intravenous area under the concentration-time curve ratio of 115 ± 8%.
JM-216 represents a unique platinum compound with excellent oral bioavailability. The chemical structure of JM-216 relative to cisplatin and carboplatin (Paraplatin) is depicted in Figure 1. A phase I study examined the pharmacokinetics of single-dose JM-216 at doses ranging from 60 to 700 mg/m2. Linear pharmacokinetics with only moderate interpatient variability were observed at doses
£ 120 mg/m2. Absorption was notably saturable at doses exceeding 200 mg/m2, and pharmacokinetics demonstrated significant variability (coefficient of variance for maximum concentration, 21% to 63%; for area under the concentration-time curve, 26% to 63%). No hematologic or nonhematologic toxicities greater than grade 2 were noted at doses
£ 200 mg/m2. In preclinical models, a single JM-216 dose was well distributed throughout liver, kidney, lung, skin, cardiac, and skeletal tissues. The liver was the major tissue depot for single-dose JM-216 in this study; hepatic concentrations were more than fivefold greater than observed for equitoxic doses of intravenous cisplatin and carboplatin.
Raynaud et al have examined the biotransformation of JM-216 following a single oral administration. Quantitation by high-performance liquid chromatography and atomic absorption spectrophotometry (AA) revealed six biotransformation species. JM-118, JM-383, and JM-518 represent the major species, while virtually no parent JM-216 was present in ultrafiltrate obtained 20 minutes following drug administration. With ovarian carcinoma cell lines, JM-118 was identified as the major cytotoxic species.
In preclinical studies, JM-216 has displayed cytotoxicity equal or superior to cisplatin and carboplatin. Kelland et al noted similar median inhibiting concentration cytotoxicity between JM-216 and cisplatin in seven ovarian carcinoma cell lines. JM-216 retained cytotoxicity in vitro against ovarian, testicular, and cervical cisplatin-resistant cell lines. Compared with equitoxic dosages of cisplatin, carboplatin, and tetraplatin (Ormaplatin), JM-216 maintained equal or superior activity against murine plasmacytoma and ovarian xenograft models in vivo. JM-216 efficacy in cisplatin-resistant cervical carcinoma cell lines was correlated with the increased intracellular accumulation of JM-216. In contrast to other platinum derivatives, a schedule-dependent effect is suggested for JM-216. In ADJ/PC6 plasmacytoma and ovarian xenograft models, a superior therapeutic index was noted when JM-216 was administered for 5 days.
Raynaud et al have examined the 5-consecutive day schedule in a phase I trial. A maximum tolerated dose of 140 mg/m2/day × 5 was observed in therapy-naive patients. Neutropenia and thrombocytopenia were the observed dose-limiting toxicities. A 14-consecutive-day schedule has been examined by Pagani et al. Thirty-three patients were treated at doses ranging from 10 to 45 mg/m2/day. One grade 3 neutropenia and two grade 4 thrombocytopenias were noted among seven patients treated at the 40 mg/m2/day dose level. Nadirs were noted 4 and 5 weeks after treatment, consistent with the prolonged terminal half-life of this platinum species. Significant cardiac, pulmonary, renal, or neurologic toxicities were not observed.
Groen et al conducted a phase II study of single-agent JM-216 in therapy-naive patients with small cell lung cancer. At a dosage of 120 to 140 mg/m2/day ×5, a 31% response rate was noted without significant renal toxicity or neurotoxicity. Phase II studies in patients with refractory ovarian, cervical, or prostate cancer are currently accruing participants at multiple investigation sites.
As extensive preclinical and clinical data exist for single-agent UFT, our discussion will be limited to phase I studies with relevant administration schedules and selected phase II data. Meropol et al examined 28-day UFT administration with concomitant leucovorin (150 mg/day in three divided doses). Previously untreated patients experienced dose-limiting diarrhea, nausea, and emesis at doses exceeding 350 mg/m2/day in three divided doses. Saltz et al evaluated a 28-day schedule with concomitant low-dose leucovorin (15 mg/day), and demonstrated acceptable toxicity at UFT doses of 350 mg/m2/day in three divided doses. Fourteen-day UFT administration schedules are currently being investigated.
A phase II, 28-day UFT study (300 to 350 mg/m2/day) in previously untreated patients with colon carcinoma revealed a response rate of 42%. Ota et al reported phase II response data for patients with several advanced solid tumors given UFT bid or tid at doses ranging from 300 to 600 mg/d. Response rates ranged from 25% to 32% in patients with colorectal cancer, cholangiocarcinoma, gastric cancer, or breast cancer.
Various combination trials using oral UFT in combination with cisplatin have been conducted. In nonsmall-cell lung cancer, UFT has been administered over 14 and 21 days with single-dose cisplatin.[24,25] Feliu et al noted a response rate of 12% with UFT 390 mg/m2/day ×14 days, but significant hematologic toxicities necessitated dose reduction in 17 of 25 patients.  Ichinose et al noted a 35% response rate in therapy-naive patients treated bid with UFT 400 mg/m2/day × 21 days, combined with single-dose cisplatin. Grade 4 myelosuppression was noted in two (6%) of 31 patients. UFT was studied in combination with cisplatin in an etoposide (VePesid)/doxorubicin (Adriamycin)/cisplatin regimen by Hayakawa et al. Patients with advanced gastric carcinoma received UFT 400 mg/m2/day × 28 days with weekly etoposide, doxorubicin, and cisplatin. An overall response rate of 47% was observed, although toxicities were substantial (grade 3 or greater leukopenia in 44.1% of patients).
Our planned phase I study will determine the feasibility and maximally tolerated doses of concomitantly administered oral UFT and JM-216. To maximize synergism, JM-216 will be administered each day with UFT over a 14-day interval. Pagani et al have demonstrated the feasibility of JM-216 administration over this protracted schedule. A maximum tolerated dose of 40 mg/m2/day was noted by these investigators; 40 mg/m2/day ×14 will thus be employed as the maximal JM-216 dose in our combination study.
The combination maximum tolerated doses for UFT and JM-216 will be determined by the dose escalation schema outlined in Table 1. At all dose levels, 90 mg/day leucovorin (30 mg tid × 14 days) will be administered with UFT. Frequent objective assessments for gastrointestinal and hematologic toxicities will be undertaken throughout the study period.
Both platinum and 5-FU are widely used to treat gastric and head and neck carcinomas. Patient convenience and continuous-exposure pharmacokinetics represent potential advantages of an all-oral regimen for these carcinomas. Preliminary single-agent JM-216 phase II data are encouraging for refractory prostate, ovarian, and cervical carcinomas. Potentiation of JM-216 cytotoxicity with combined UFT administration may therefore have phase II applications in these solid tumors. The radiosensitizing effects of continuous infusion 5-FU are established in head and neck, pancreatic, bladder, and anal carcinomas. A regimen of concomitant oral UFT/JM-216 and radiation may therefore deserve investigation in these clinical settings.
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