Detail of "72732-56-0"

Reference

Drug concentration-dependent DNA lesions are induced by the lipid-soluble antifolate piritrexim (BW301U)

Drug concentration-dependent DNA lesions are induced by the lipid-soluble antifolate piritrexim (BW301U). Richards, Randall G.; Brown, Oliver E.; Gillison, Maura L.; Sedwick, W. David (Med. Cent., Duke Univ., Durham, NC 27710, USA). Mol. Pharmacol., 30(6), 651-8 (English) 1986. CODEN: MOPMA3. ISSN: 0026-895X. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The lipid-sol. folic acid [59-30-3] antagonist piritrexim (I) [72732-56-0] induced misincorporation of dUMP [964-26-1] in human B (SB)- and T (MOLT-4)-lymphoblastoid cells, and in human promyelocytic leukemia cells (HL-60). Anal. by alk. sucrose gradients and alk. elution indicated that [3H]DNA that had been labeled for 15 min was distributed into progressively smaller DNA fragment sizes in a drug concn.-dependent manner from 0 mM to 50 mM piritrexim. This phenomenon was obsd. regardless of the labeled nucleotide precursor employed for detection of newly synthesized DNA ([3H]deoxyuridine, [3H]deoxyadenosine, or [3H]deoxycytidine). In contrast, H2CO denaturation and sedimentation of DNA in neutral denaturing sucrose gradients released only 3-4% of the newly synthesized DNA as 3-6 S fragments (80-200 nucleotides), whereas the remaining population of newly synthesized DNA pelleted to the bottom of the tube. Failure to detect DNA fragmentation under neutral conditions to the extent obsd. under alk. conditions indicated the presence of apurinic and apyrimidinic sites in DNA lesions, which would be expected in DNA undergoing excision-repair of misincorporated dUMP. Cytotoxicity resulting from dUMP misincorporation was consistent with the enhanced toxicity of piritrexim which was obsd. when HL-60 cells or MOLT-4 cells were exposed concurrently to exogenous deoxyuridine [951-78-0]. Deoxyuridine-enhanced toxicity was concn. dependent for both cell lines when piritrexim concns. were marginally toxic. The cytotoxic effect of dUMP misincorporation was further substantiated by the observation that MOLT-4 cells treated with 0.5 mM piritrexim alone eventually developed resistance to the drug, whereas treatment with both piritrexim and 10 mM deoxyuridine prevented the selection of piritrexim-resistant cells.

Selective toxicity of a new lipophilic antifolate, BW301U, for methotrexate-resistant cells with reduced drug uptake

Selective toxicity of a new lipophilic antifolate, BW301U, for methotrexate-resistant cells with reduced drug uptake. Taylor, Ian W.; Slowiaczek, Peter; Friedlander, Michael L.; Tattersall, Martin H. N. (Ludwig Inst. Cancer Res., Univ. Sydney, Sydney 2006, Australia). Cancer Res., 45(3), 978-82 (English) 1985. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Three methotrexate (MTX) [59-05-2]-resistant cell lines and their MTX-sensitive counterparts were used to examine BW301U (I) [72732-56-0], a novel lipophilic antifolate, and compare its cytotoxicity with MTX and metoprine. Collateral sensitivity for both BW301U and metoprine was obsd. in CCRF-CEM/MTX R-cells, where MTX resistance appeared to be primarily due to a deficiency in drug uptake. This was particularly pronounced with BW301U which proved to be as effective in killing CCRF-CEM/MTX R as was MTX with the parental CCRF-CEM cell line. This effect was not seen in other cell lines, L5178Y/MTX or L1210/MTX R, where resistance to MTX was correlated with either an overprodn. of 5,6,7,8-tetrahydrofolate:NADP oxidoreductase EC 1.5.1.3 (DHFR) or with combined uptake defect and increased DHFR levels, resp. In each case, however, BW301U and metoprine, esp. at high concns., were more effective than MTX in treating MTX-resistant cells.