Biomedical subjects

C Takimoto

Publications and source records attributed to C Takimoto.

7 recordsLinked to original sources

PubMed2001

Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. RESULTS: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL). CONCLUSION: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

Administration, Oral↗

PubMed1999

Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells.

The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3,000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1,000-fold more resistant to topotecan, 9-amino-20(S)-camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), than their parental cell lines. The cell lines demonstrated much less resistance to camptothecin and to several camptothecin analogues. Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after camptothecin treatment. In addition to topotecan and SN-38, MXR-overexpressing cells are highly resistant to mitoxantrone and epirubicin. Because these compounds are susceptible to glucuronidation, we examined UDP-glucurono-syltransferase (UGT) activity in parental and resistant cells by TLC. Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A family mRNAs. We thus conclude that colon and breast cancer cells have a capacity for glucuronidation that could contribute to intrinsic drug resistance in colon cancer cells and may be acquired in breast cancer cells. The lack of selection for higher levels of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the camptothecins.

ATP-Binding Cassette Transporters↗

PubMed1999

A pilot study of interferon alpha-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma.

We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5-fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (J. L. Grem et al., J. Clin. Oncol., 12: 560-568, 1994). We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/IFN-alpha (IFN alpha-2a). Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN alpha(-2a (5 MU/m2 s.c., days 1-7), 5-FU (370 mg/m2 i.v., days 2-6), LV (500 mg/m2 i.v., days 2-6), and GM-CSF (Saccharomyces cerevisiae 250 microg/m2 s.c., days 7-18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN alpha-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737-1745, 1993). In comparison with the prior Phase II study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4%), and 13 (46%) had stable disease for > or =12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study. No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival. The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN alpha-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined.

Adenocarcinoma↗

PubMed1998

Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates.

PURPOSE: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. METHODS: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. RESULTS: 9-AC lactone had a clearance (CL) of 2.1 +/- 0.9 l/kg per h, a volume of distribution at steady state (Vd[ss]) of 1.6 +/- 0.7 l/kg and a half-life (t1/2) of 3.2 +/- 0.8 h. The lactone form of 9-AC accounted for 26 +/- 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC(CSF):AUC[P]) was only 3.5 +/- 2.1%. For irinotecan, the CL was 3.4 +/- 0.4 l/kg per h, the Vd(ss) was 7.1 +/- 1.3 l/kg, and the t1/2 was 4.9 +/- 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 +/- 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 +/- 6% of the total SN-38 in plasma. The AUC(CSF):AUC(P) ratio for irinotecan lactone was 14 +/- 3%. SN-38 lactone and carboxylate could not be measured (< 1.0 nM) in CSF. The AUC(CSF):AUC(P) ratio for SN-38 lactone was estimated to be < or = 8%. CONCLUSION: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF):AUC(P) ratio of 32%.

Animals↗

PubMed1997

Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity.

Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid found in soy beans, has been identified as potentially causal for the low incidence of metastatic prostate cancer (PCa) in certain countries. Although genistein-induced PCa cell adhesion has been identified as a possible causative mechanism, direct growth inhibition by genistein has been reported and also could be causal. If in vivo growth inhibition was significant, then growth inhibition should occur at concentrations attained with dietary consumption, the mechanism of growth inhibition should be relevant to PCa, and genistein (a broad-spectrum in vitro protein-tyrosine kinase inhibitor) should have relatively specific kinase inhibitory effects in vivo. These considerations were investigated by measuring growth inhibitory activity in a variety of PCa cell lines. Growth inhibitory effects were shown not to occur with concentrations below the low micromolar range (i.e., 3 logs above that attained in serum). In-depth mechanistic studies with the PC3-M metastatic variant cell line demonstrated that growth inhibition was independent of genistein's estrogenic effects. Genistein was shown to decrease the viability of nonadherent cells, suggesting a lack of dependence on cell adhesion for growth inhibition. However, important molecular and kinetic differences between genistein's effects on growth in adherent versus nonadherent cells were identified. Specific suppression of focal adhesion kinase activity (without global decreases in phosphotyrosine) was shown to precede induction of apoptosis, which was responsible for growth inhibition in adherent cells. These findings do not support an in vivo growth inhibitory role by genistein consumed in quantities associated with a soy-based diet. They do, however, identify genistein as a potential therapeutic agent for PCa and as a tool with which to study the control of apoptosis in PCa.

Apoptosis↗

PubMed1996

Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients.

PURPOSE: To conduct a phase I and pharmacologic study of the new topoisomerase I inhibitor, 9-aminocamptothecin (9-AC). PATIENTS AND MATERIALS: A 72-hour infusion of 9-AC was administered every 14 days to 48 solid-tumor patients at doses of 5 to 59 microg/m2/h without granulocyte colony-stimulating factor (G-CSF) and 47 to 74 microg/m2/h with G-CSF. RESULTS: Without G-CSF, two of eight patients who received 47 microg/m2/h had dose-limiting neutropenia in their initial cycle, as did both patients who received 59 microg/m2/h (with a platelet count < 25,000/microL in one). With G-CSF, zero of seven patients treated with 47 microg/m2/h had dose-limiting neutropenia in their first cycle, while dose-limiting neutropenia occurred in six of 14 patients (with platelet count < 25,000/microL in five) entered at 59 microg/m2/h. Among 39 patients entered at > or = 25 microg/m2/h 9-AC with or without G-CSF, fatigue, diarrhea, and nausea/vomiting of grade 2 severity ultimately occurred in 54%, 30%, and 38%, respectively, while grade 3 toxicities of each type occurred in 8% of patients. Steady-state 9-AC lactone concentration (Css) increased linearly from 0.89 to 10.6 nmol/L, and correlated strongly with leukopenia ( r = .85). CONCLUSION: The recommended phase II dose of 9-AC given by 72-hour infusion every 2 weeks is 35 microg/m2/h without G-CSF or 47 microg/m2/h with G-CSF support. Dose escalation in individual patients may be possible according to their tolerance.

Adult↗

PubMed1982

[Efficacy of arterial infusion chemotherapy with neocarzinostatin on inoperable hepatoma].

The characteristic of a slow infusion technique of angiography provided a new method of selective intraarterial administration. We named this new method "high pressure one hot injection." When we tried to apply this method to patients with inoperable hepatoma, we considered that Neocarzinostatin (NCS) was a very applicable antitumor drug in terms of cell killing kinetics. Fifteen patients with inoperable hepatoma were treated with NCS by the selective intra-hepatic arterial infusion method. Administration of NCS was given by using a technique of high pressure one shot injection. The administration dose of NCS was 6000u. or 10000u., and 10 patients received once, and the others twice or three times. Results were as follows: 1) According to both Karnofsky's criteria and the criteria of direct response for solid cancer, an objective response was observed in 6 patients (40%). In proportion to the increase of the total dose and frequencies the individual efficacy increased. 2) The median survival was 5.5 months. 3) Decrease of serum AFP was seen, prominently within one month after injection. 4) The major side effects were fever (93%), liver dysfunctions (53%), leukopenia (46%), thrombocytopenia (33.3%), and their frequencies were related to the dose of one injection and that of the total. These results suggest that the high pressure one shot injection of NCS is very effective to inoperable hepatoma, but both dose and interval of injection remain to discussed.

Adult↗