High‐dose intravenous and hepatic artery infusions of thymidine

Abstract

Thymidine (TdR) was administered by constant infusion at progressively escalated dose rates to 4 patients with colon cancer metastatic to liver in whom hepatic arterial (HA) and hepatic venous (HV) catheters had been placed. Serum levels ofTdR and hepatic extraction ofTdR were determined as a function of dose rate. With intravenous infusions, serum levels of TdR rose progressively with dose rate, going from 1.3 to 3.4 µM at 8 gm/M2/day to 1,200 µM at 128 gm/M2/day. The hepatic extraction ratio at dose rates up to 16 gm/M2/day was high, ranging from 0.64 to 0.95, but when, as was done in one patient, dose rates were increased from 16 gm/M2/day to 128 gm/M2/day, the extraction ratio fell progressively from 0.85 to 0.17. With direct HA infusion hepatic extraction ofTdR was high (94% to 98%) at 8 gm/M2/day, but fell progressively as dose rates were increased to 16 gm/M2/day and 32 gm/M2/day. Thus, it appears that, though efficient, hepatic extraction processes for TdR are saturable. Our data also suggest that high TdR levels falling in millimolar ranges, such as have been shown previously to induce cytotoxicity in preclinical models, are achievable by peripheral intravenous infusions at dose rates of 64 to 128 gm/M2/day and that selectively higher hepatic levels can be maintained at dose rates of 16 to 32 gm/M2/day by HA infusions.

Regional chemotherapy of neoplastic diseases

“…Although the data is limited, significantly (i.e. > 2-fold) increased exposure with hepatic arterial infusion is seen for a number of other agents including dichloromethotrexate (Ensminger et al, 1981b), thymidine (Ensminger and Frei, 1978), bischlorethylnitrosourea (Ensminger et al, 1978b), mitomycin C (Tseng et al, 1981), and cis-platinum (Kelsen et al, 1980). The theoretical principles described above assume that the rate coefficients of drug loss remain constant over the complete range of drug concentrations and throughout the time periods involved.…”

“…The theoretical principles described above assume that the rate coefficients of drug loss remain constant over the complete range of drug concentrations and throughout the time periods involved. Data obtained with increasing dose rates of thymidine given into the hepatic artery demonstrate that extraction processes can become increasingly saturated with the hepatic extraction dropping from 80~o at 4 g/m: per day to less than 20~ at 128 g/m 2 per day (Ensminger and Frei, 1978). Non-linear pharmacokinetics with saturable elimination also apparently hold for infusions of the radiosensitizer 5-bromo-2'-deoxyuridine (Sonneveld et al, 1982).…”

Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.

“…Synergy was demonstrable across a broad spectrum ofdrug effect, ranging from concentrations that reduced the net growth rate to zero to concentrations that killed 90% ofthe cells in the culture. These concentrations encompass a range that is readily achieved in patients (39)(40)(41)(42)(43). In addition, the results indicate that dThd and HU interact synergistically, so that the triple combination of Ara-C, dThd, and HU is synergistic.…”

“…Cells were exposed to the. clinically achievable concentrations of 1 mM dThd (39)(40)(41) and HU (42), and 0.1 ,uM Ara-C (43). The effects of dThd were qualitatively and quantitatively different in SB cells than in the leukemic blasts.…”

Clinical use of thymidine as a rescue agent from methotrexate toxicity

“…The MTD is 75-80 g/m2/d as a CI lasting 3 to 7 days in patients with solid tumors, and CPs s of 1 to 2 mM are achieved [30][31][32][33][34]. Dose limiting toxicity involved the CNS (headache, confusion, somnolence), gastrointestinal tract (anorexia, nausea, vomiting and diarrhea), and bone marrow (leukopenia).…”