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At least 19 recordsLinked to original sources
PubMed2026

Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.

PURPOSE: Transforming growth factor β (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in the disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials. PATIENTS AND METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve patients with metastatic PDAC (mPDAC) to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel (or Abraxane)/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cell-free DNA profiling, and plasma proteomics. RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of cancer-associated fibroblast markers (Acta2, Fap) and collagen-related signatures. Despite proof of mechanism, clinical efficacy was not observed: Median PFS and OS were comparable or numerically worse in the NIS793 arm versus control (HR for OS in NIS793 + ABRA/GEM vs. ABRA/GEM: 1.32; 95% confidence interval, 0.84-2.07). The safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition.

Humans↗
PubMedDate not supplied

Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs.

Gemcitabine, 2'-deoxy-2',2'-difluorocytidine, is a broad spectrum oncolytic compound with antitumor activity in solid tumor models. The pharmacokinetics, metabolism, and disposition of gemcitabine was examined in mice, rats, and dogs. All three species metabolize gemcitabine by deamination to the uracil metabolite. However, deamination in the mouse and dog was more extensive than in the rat. The mouse deaminated gemcitabine rapidly with the plasma concentration maximum of the uracil metabolite of gemcitabine being attained at 15 min postdosing compared with approximately 3 and 6 hr in the dog and rat, respectively. The rapid deamination in the mouse was also reflected in the plasma half-life of the parent compound. The mouse exhibited the shortest plasma half-life, approximately 0.28 hr, contrasted with 2.14 and 1.38 hr half-lives in rat and dog, respectively. Plasma AUC for the uracil metabolite of gemcitabine was 73%, 10.5%, and 315% of that for gemcitabine in the mouse, rat, and dog, respectively. Tissue concentrations of gemcitabine-derived radioactivity in the rat and mouse indicated that gemcitabine was rapidly distributed throughout the body. Half-lives of radioactivity in tissues of both the rat and mouse were relatively short, with the longest tissue half-lives of 5.7 and 3.0 hr, respectively. Plasma protein binding is negligible in all three species. The major route of elimination is via the urine in all three species with 76-86% of the dose excreted in the first 24 hr. The predominant radiolabeled component isolated from urine was gemcitabine in the rat and its uracil metabolite in the mouse and dog.

Animals↗
PubMed2026

3D epigenomic remodelling mediated by Foxa1 drives gemcitabine resistance in pancreatic cancer.

Gemcitabine remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet the emergence of resistance constitutes a major clinical challenge with poorly understood epigenomic mechanisms. Here, we identified the pioneer transcription factor Foxa1 as a master regulator of gemcitabine resistance through multi-omics analysis. Mechanistically, Foxa1 drives widespread super-enhancer (SE) reprogramming and 3D genome remodelling in resistant cells, which coordinately activates the expression of key resistance genes, notably Rrm1 and Cdadc1. This is accompanied by increased chromatin accessibility, elevated H3K27ac enrichment at SEs, and enhanced Foxa1 binding at regulatory elements. Moreover, post-translational stabilization of Foxa1 via USP7-mediated deubiquitination sustains this epigenomic program. Genetic ablation of Foxa1 or specific SE regions near Rrm1 resensitizes resistant cells to gemcitabine. Building upon this mechanism, we demonstrate that bromodomain and extraterminal (BET) inhibitors, which disrupt SE function, potently reverse resistance. Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC.

Hepatocyte Nuclear Factor 3-alpha↗
PubMed2026

Penpulimab and Gemcitabine With or Without Anlotinib in Metastatic Nasopharyngeal Carcinoma: A Randomized, Open-Label, Multicenter Phase 2 Study.

This prospective exploratory phase 2 study employed a three-cohort, two-phase design to evaluate the potential of anlotinib as a substitute for cisplatin in gemcitabine-penpulimab combinations for metastatic nasopharyngeal carcinoma (NPC) patients who were previously treated with cisplatin-based chemoradiotherapy. Patients enrolled in the study were randomized in a 1:1:1 ratio during the lead-in phase to one of three treatment arms: gemcitabine, cisplatin, penpulimab, and anlotinib (GP-PA, n = 8); gemcitabine, cisplatin, and penpulimab (GP-P, n = 6); or gemcitabine, penpulimab, and anlotinib (GAP, n = 6). The expansion phase enriched the optimal cohort, with stratification based on PD-L1 expression. The primary endpoints were safety and objective response rate (ORR), while the secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). In the lead-in phase, grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 87.5% (GP-PA), 100% (GP-P), and 66.7% (GAP) patients, predominantly hematologic toxicities. ORR/DCR were 62.5%/87.5% (GP-PA), 83.3%/100% (GP-P), and 100%/100% (GAP). At median 20.2-month follow-up, median PFS/OS were 4.1/18.4 months for GP-PA and not reached for GP-P/GAP. In the expansion phase, a total of 14 patients received GAP, with an ORR of 93.3% and grade ≥ 3 TEAEs in 71.4% of patients. At data cut-off point, the median PFS had not been reached, and the 12-month PFS and OS rates were 53.8% and 78.6%, respectively. The GAP regimen demonstrated a favorable safety and efficacy profile, compared to the GP-PA and GP-P regimens in patients with metastatic NPC. These findings suggest that substituting cisplatin with anlotinib may offer a viable therapeutic strategy for this patient population.

Humans↗
PubMed1992

[New antitumor antimetabolites--gemcitabine and DMDC].

Gemcitabine (dFdC) and DMDC are new antimetabolites with good antitumor activities against various tumors which include human leukemic cell lines and a number of rodent and human solid tumors and human tumor. They are structurally related to cytarabine (Ara-C) which is known as one of the most effective drugs against adult acute leukemia, but many solid tumors are insensitive not been found to the drug. Gemcitabine acts as an inhibitor of ribonucleoside diphosphate reductase and inhibits DNA synthesis. Biochemically Gemcitabine is rapidly phosphorylated to dFdCTP which has a comparatively longer half-life than that of Ara-C, showing a therapeutic activity against tumors. In the phase I trials, the reported maximum-tolerated doses were 790 mg/m2 to 1370 mg/m2 at the schedule of 30 minutes i.v. infusion once a week for three weeks but higher dose levels (2,500 mg/m2 to 4,800 mg/m2) were reported in the schedule of prolongation of the infusion time. Reported toxicities were myelosuppression, fatigability, fever, appetite loss and skin rash. Toxicities were seemed to be mild. In USA, Europe and South Africa, phase II trials of Gemcitabine at the schedule of 30 minutes infusion once a week for three weeks followed by one week rest were performed against solid tumors (breast cancer, ovarian cancer, renal cancer, colorectal cancer, pancreas cancer, head and neck cancer, and lung cancer) and showed good responses to those tumors. DMDC was developed in Japan, and a phase I trial is currently on-going.

Animals↗
PubMed1992

Phase II study of gemcitabine in advanced colorectal adenocarcinoma.

A phase II trial of gemcitabine (difluorodeoxycytidine) was conducted in 14 patients with advanced colorectal adenocarcinoma. Gemcitabine was administered intravenously over 30 minutes at weekly intervals for 3 consecutive weeks each month. The starting dose was 800 mg/m2, with dose escalation as tolerated. No complete or partial response were observed. Ten patients experienced progressive disease while on therapy. Toxic effects were primarily hematologic in nature. Grade 3 toxicities included leukopenia (one patient at 1000 mg/m2), granulocytopenia (two patients at 800 mg/m2), anemia (two patients at 800 mg/m2), and myalgia (one patient at 800 mg/m2). No grade 4 toxic effects or treatment-associated deaths were observed. Gemcitabine, at the doses and schedule used in this study, did not demonstrate activity against advanced colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed1992

Activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human tumor colony forming units.

2',2'-Difluorodeoxycytidine (LY 188011, Gemcitabine) is a novel pyrimidine antimetabolite with promising activity in preclinical models for leukemia and solid tumors. Phase I clinical trials with the agent are ongoing. In order to better define types of tumors with clinical sensitivity to Gemcitabine (to help target phase II trials), we have studied the antitumor effects of this agent against a variety of freshly explanted human tumor specimens using an in vitro capillary soft agar cloning system. Final concentrations of 2.0-200 micrograms/ml were used for short-term (1 h) and continuous incubations experiments. Using a short-term incubation, 94/215 (44%) tumor specimens were evaluable for the determination of antitumor activity. The most common tumor types studied included colorectal, breast, non-small cell lung, ovarian cancer, kidney and melanoma. A concentration-dependent increase in the frequency of inhibited tumor specimens was noted (2 micrograms/ml: 6/94 specimens, 20 micrograms/ml: 13/94 specimens, 200 micrograms/ml:33/94 specimens; p less than 0.0001). A similar increase in tumor growth inhibition was found using a continuous incubation (2 micrograms/ml: 0/14 specimens, 20 micrograms/ml: 1/14 specimens, 200 micrograms/ml: 7/14 specimens; p less than 0.001). We conclude that Gemcitabine is an active antitumor agent against tumor colony forming units from a variety of human malignancies if sufficiently high concentrations can be achieved. The agent should be evaluated for Phase II clinical activity against those tumor types.

Antimetabolites, Antineoplastic↗
PubMed1992

Deoxycytidine protects normal bone marrow progenitors against Ara-C and gemcitabine cytotoxicity without compromising their activity against cisplatin-resistant human ovarian cancer cells.

The intracellular metabolism and cytotoxic effects of Ara-C and 2'-difluorodeoxycytidine (dFdC or Gemcitabine) administered with or without deoxycytidine (dCyd) were examined in cisplatin-resistant (2008/C13) and -sensitive (2008) human ovarian cystadenocarcinoma cells. Compared to 2008 cells, 2008/C13 cells possess 2.1-fold higher glutathione (GSH) levels, enhanced expressions of GSH S-transferase (GST)-pi mRNA and protein, and significantly greater activity of GST, GSH peroxidase, and GST reductase. Although 2008/C13 cells were slightly cross-resistant to 4-hydroperoxycyclophosphamide, the drug displayed a steep dose-response (colony growth inhibition) effect toward these cells. 2008/C13 cells expressed greater sensitivity toward Ara-C and Gemcitabine. This was associated with intracellular Ara-CTP and dFdCtriphosphate levels in 2008/C13 significantly higher than those in 2008 cells. Against bone marrow progenitor cells, the cytotoxic effects of submicromolar levels of Ara-C or dFdC, produced in plasma following intraperitoneal administration of the drugs, were significantly reversed by cotreatment with high levels of dCyd achieved in plasma following intravenous administration. In contrast, the metabolism and cytotoxic effects of Ara-C and dFdC in 2008 and 2008/C13 cells were not significantly altered by dCyd concentrations that are reached in the peritoneum following intravenous administration. These in vitro data suggest that systematically administered dCyd might protect bone marrow progenitor cells against Ara-C cytotoxicity without impairing antitumor activity of intraperitoneal Ara-C.

Antimetabolites, Antineoplastic↗
PubMed2026

Resveratrol Attenuates Gemcitabine Resistance in Hepatocellular Carcinoma Cells by Inhibiting Thymidylate Synthase.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Gemcitabine (Gem) is a commonly used drug against HCC, but its efficacy is limited by the development of resistance. Resveratrol (Res), a natural polyphenol with antitumor activity, may reverse Gem resistance in HCC, although the mechanism remains unclear. METHODS: The effects of Res on the proliferation, apoptosis, cell cycle, and invasion of Hep3B and HuH-7 cells were assessed via cell counting kit-8 (CCK-8), clonogenic, flow cytometry, and Transwell assays, respectively. Potential Res targets were predicted by network pharmacology, and markers of HCC prognosis were identified from the cancer genome atlas (TCGA) data. The interaction between Res and thymidylate synthase (TYMS) was validated by molecular docking and dynamics simulation. A Gem-resistant HuH-7 cell line (HuH-7/GR) was established, and when these cells were treated with Res combined with Gem, the effect on Gem sensitivity was detected by CCK-8 assay, clonogenic assay, and flow cytometry. Finally, a subcutaneous nude mouse model of HCC was used to evaluate the in vivo effects of Res combined with Gem. RESULTS: Res inhibited HCC cell proliferation, induced apoptosis and G2/M arrest, and suppressed invasion in a concentration-dependent manner. Network pharmacology and TCGA analysis identified TYMS as an important target gene for Res. TYMS was highly expressed in HCC tissues and correlated with poor prognosis. Res treatment reduced TYMS expression, while molecular docking and simulation showed stable binding of Res to TYMS. TYMS levels were elevated in HuH-7/GR resistant cells. Res combined with Gem was found to reverse drug resistance, inhibit proliferation and colony formation, and induce apoptosis. The Res + Gem combination group showed the smallest tumor volume in the in vivo model. CONCLUSION: By attenuating Gem resistance through TYMS inhibition, Res holds promise as a clinically viable adjunct to Gem-based chemotherapy, offering a potential strategy to improve outcomes in HCC patients.

Resveratrol↗
PubMed1991

Saturation of 2',2'-difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine.

The plasma and cellular pharmacology of 2',2'-difluorodeoxycytidine (dFdC, Gemcitabine) was studied during a phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m2 per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5'-triphosphate (dFdCTP), were determined in mononuclear cells of 22 patients by anion-exchange high-pressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m2 per 30 min, during which steady-state dFdC levels of 15-20 microM were achieved in plasma. A comparison of patients infused with 800 mg/m2 over 60 min with those receiving the same dose over 30 min demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10-15 microM dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable. In the design of future protocols, a dose rate should be considered that produces maximal nucleotide analogue formation, with increased intensity being achieved by prolonging the duration of infusion.

Antimetabolites, Antineoplastic↗
PubMed1991

A phase I clinical, plasma, and cellular pharmacology study of gemcitabine.

A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.

Adult↗
PubMed1992

Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study.

PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS: The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS: The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION: Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.

Adolescent↗
PubMed1991

Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human head and neck cancer.

2',2'-Difluorodeoxycytidine (dFdCyd, Gemcitabine) is a new deoxycytidine analogue with striking preclinical antitumor activity in solid tumors from murine and human origin. In this study, dFdCyd was tested for its antitumor effect in human tumor xenografts derived from squamous cell carcinoma of the head and neck (SCCHN). NMRI nude mice bearing s.c. growing tumors with a volume of 50 to 150 mm3 were given i.p. injections of a maximum tolerated dose of 120 mg/kg dFdCyd, every 3 days for four injections. A significant antitumor effect was observed in all five tested SCCHN tumor lines; in four of these lines the median tumor volume doubling time increased more than a 3-fold upon dFdCyd treatment. In two lines dFdCyd was curative (no tumor regrowth 90 days after treatment) in one of six and two of eight xenografts, respectively. Schedule dependency was investigated in three SCCHN lines, showing, in the two most sensitive lines, that treatment with a 3-day interval was superior to the schedules with daily or weekly injections. At equitoxic doses, dFdCyd was more active in this model than the drugs that are clinically used in SCCHN, i.e., cisplatin, methotrexate, 5-fluorouracil, and cyclophosphamide. dFdCyd is a good candidate for clinical trials with SCCHN patients.

Animals↗
PubMed1990

Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine).

A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.

Animals↗
PubMed1992

Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study.

Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.

Adult↗
PubMed1990

Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (Gemcitabine) administration in leukemia.

The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 microM during infusion of 800 mg/m2/h, 9.4 microM during infusion of 400 mg/m2/h, and 5.6 microM at 267 mg/m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 2.3- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5-100 microM dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15-20 microM dFdC. We conclude that a dose rate of greater than 400 mg/m2/h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.

Adult↗