Cancer Chemotherapy and Pharmacology

Uridine (UR) inhibits the metabolic activation of 5′-deoxy-5-fluorouridine (dFUR) to 5-fluorouracil (FU) by the intestinal pyrimidine nucleoside phosphorylases and could potentially reduce its intestinal toxicity. This study examined the effect of UR coadministration on the absorption and disposition of an oral dose of dFUR. Rats were given dFUR alone (500 mg kg-1) and dFUR (300 mg kg-1) plus UR (4.5 g kg-1) in a random crossover experiment. Simultaneous injection of a tracer dose of [6-3H]dFUR was used to asses the total body clearance (Cl) of dFUR. The absorption of UR was rapid and variable. The UR dose produced a maximal blood concentration of 80 μg/ml for UR and 100 μg/ml for its metabolite uracil (U). The absorption of dFUR was slower than UR, as indicated by its later time of maximal concentration. UR did not alter the Cl of dFUR, but reduced the absorption rate of dFUR from the gastrointestinal tract and significantly reduced the absolute oral bioavailability of dFUR from 55.2% to 33.4%. The effects of UR coadministration on the dFUR metabolite FU were opposite to those on dFUR; the FU availability was increased sixfold, and the elimination of FU was reduced. Based on the known competition between pyrimidine bases for their saturable metabolic enzymes, the increase in FU availability by UR coadministration was likely due to a competitive inhibition of FU metabolism by U. This study established the complex pharmacokinetic interactions between dFUR and UR and between their metabolites, which may be important in the modulation of dFUR activity by UR.

Rapidly dividing tumor cells have an increased demand for nutrients to support their characteristic unabated growth; this demand is met by an increased availability of nutrients such as amino acids through vasculogenesis and by the enhanced cellular entry of nutrients through the upregulation of specific transporters. Deprivation of intracellular amino acids or block of amino acid uptake has been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft models. In this paper, we provide evidence that the two small molecule oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2α as well as mTOR pathway inhibition supports the above notion. In addition, these novel anti-cancer compounds inhibit DNA and protein synthesis and induce apoptosis in a broad spectrum of cancer cell lines. In vivo, the compounds induce tumor stasis and regression in mouse xenograft models of human breast, prostate, ovarian and pancreatic cancer, both when administered intravenously and orally. In conclusion, these small molecules, built on a 1,3-dihydroindole-2-one scaffold, elicit strong anti-proliferative and cytotoxic activity, and importantly, a strong anti-tumorigenicity is observed in in vivo xenograft models of human breast, ovary, prostate and pancreatic cancers encouraging the translation of this class of compounds into the clinic.

17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) is a water-soluble analogue of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in clinical trials. These preclinical studies: (1) characterized 17DMAG concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice; and (2) correlated tumor and normal tissue 17DMAG concentrations with alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned proteins. At specified times after i.v. administration of 75 mg/kg 17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed and plasma and tissues were retained. 17DMAG concentrations were determined by HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined by Western blotting. Peak plasma 17DMAG concentration was 15.4±1.4 μg/ml. The area under the plasma 17DMAG concentration versus time curve was 1072 μg/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8±5.7 μg/g), kidney (122.9±10.6 μg/g), heart (81.3±8.1 μg/g), and lung (110.6±25.4 μg/g) occurred at 5–10 min, while peak concentrations in spleen (70.6±9.6 μg/g) and tumor (9.0±1.0 μg/g) occurred at 30–45 min. At 48 h, 17DMAG was detectable in tumor but not in any normal tissue. Raf-1 in tumors of 17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated animals were significantly lower than in tumors of control animals at 4, 7, and 24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50% at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold above that in kidneys from vehicle-treated control mice at 7 and 24 h, while HSP90 relative protein concentration was no different from that in controls. Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were similar to those previously reported in nontumor-bearing mice. 17DMAG was distributed widely to tissues but was retained for longer in tumors than normal tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors, livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex nature of the biological responses to 17DMAG.

The objectives of this phase I study were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of intraperitoneally administered irinotecan (CPT-11) in gastric cancer patients with peritoneal seeding. Gastric adenocarcinoma patients with surgical biopsy proven peritoneal seeding were enrolled at the time of surgery. Prior to IP chemotherapy, patients underwent palliative gastrectomy and CAPD catheter insertion in which CPT-11 was administered on postoperative day 1. The IP CPT-11 was initiated at 50 mg/m2, which was escalated to 100, 150, 200, 250, and 300 mg/m2. IP CPT-11 chemotherapy was repeated every 3 weeks. Seventeen patients received a total of 56 cycles at five different CPT-11 dose levels. The DLTs were neutropenic fever, neutropenia, and diarrhea. At the dose level 2 (100 mg/m2), there were one DLTs in one of the first cohort of three patients, but no DLTs at the second cohort of this level. At the dose level 5 (250 mg/m2), two DLTs were detected in the first two patients; thus, the accrual was stopped resulting in the recommended dose of IP CPT-11 of 200 mg/m2. Median progression-free survival was 8.6 months (95% CI, 5.9,11.2), and median overall survival was 15.6 months (95% CI, 8.4,22.8). Pharmacokinetic results of the study showed that the C max of peritoneal SN-38 was achieved earlier than that of plasma SN-38. Intraperitoneally administered CPT-11 was feasible and tolerable. Further, phase II study of IP CPT-11 in gastric cancer patients with peritoneal seeding is warranted.

To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin. A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure–response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models. Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure–response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 –NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325–486). The amatuximab exposure showed similar significant effect on PFS. Exposure–response analysis for adverse events did not reveal any relationship. In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

 A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m2 of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m2 UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m2 was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m2) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (Cmax 1.4±1.9 μM) were comparable to those achieved with protracted venous infusions, and folate levels (Cmax 6.1±3.6 μM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs.

A case of acute nonlymphocytic leukemia (ANLL) following chemotherapy with cisplatin (CDDP) and etoposide (VP16) for non-small-cell lung cancer (NSCLC) diagnosed 24 months before is reported. Although the fortuitous occurrence of two unrelated malignancies cannot be excluded, the hypothesis of secondary leukemia must be taken into account. The clinical and experimental data implying these agents, generally considered to be noncarcinogenic in man, in the occurrence of secondary malignancies are briefly discussed.

Testing of new drugs in small-cell lung cancer is definitely necessary for the development of agents that might be effective against this tumor. However, testing such drugs in previously untreated patients with a good performance status (PS) may give rise to ethical problems. When previously treated patients are used in testing, potentially effective agents could well elude discovery. Patients who are not eligible for “standard” combination chemotherapy, e.g. untreated patients with a poor PS, may be suitable for testing of new drugs. To evaluate the potential usefulness of such patients in the testing of new agents, we evaluated an effective drug (etoposide) at a relatively nontoxic dose in a group of 14 patients with a PS of 4 (WHO). Oral etoposide resulted in a response in only 3 cases, whereas 5 subjects died of therapy-related toxicity. We conclude that previously untreated patients with a poor PS are not suitable candidates for the testing of new drugs.