Sites of Action of Amethopterin: Intrinsic and Acquired Drug Resistance

Studies Concerned with Overcoming Resistance to Methotrexate: A Comparison of the Effects of Methotrexate and 2,4-Diamino-5-(3′,4′-Dichlorophenyl)-6-Methylpyrimidine (BW50197) on the Colony Forming Ability of L5178Y Cells

“…Because diaminopyrimidines had been shown to possess antitumour activity and since BW50197 appeared superior in certain experimental systems, we felt that this compound merited further study. In this report we (Harrap et al, 1971). These cells can still be killed provided that a sufficient extracellular concentration of the drug can be maintained for a long enough time (Harrap et al, 1971).…”

“…In this report we (Harrap et al, 1971). These cells can still be killed provided that a sufficient extracellular concentration of the drug can be maintained for a long enough time (Harrap et al, 1971). Clinically, however, a prolonged exposure to MTX is associated with severe toxicity to normal proliferating systems such as the bone marrow and gut (Bergsagel, personal communication 1970), although very high concentrations can safely be given over short periods of time (Goldie, Price and Harrap, 1972;Djerassi et al, 1,972).…”

Antigenicity and drug susceptibility of human osteogenic sarcoma cells “escaping” a cytotoxic methotrexate-albumin-monoclonal antibody conjugate

“…The behaviour of the tumour cells themselves in response to the conjugate will also determine its overall therapeutic efficacy. In conventional cancer chemotherapy the development of resistance to drugs, such as MTX, is a common problem (Harrap et al, 1971) and this is equally possible in the case of drug-antibody conjugates. In addition, there is the possibility that tumour cells might lose antigen expression, either by selection of non-antigenic clones or by antibody-induced modulation, and consequently fail to bind sufficient conjugate to achieve cytotoxicity.…”

Renal Glycoprotein: Glycosyl Transferase Activities after Administration of Folic Acid

“…Similar in vitro results were obtained with methotrexate, but not with 5-formyl tetrahydrofolic acid. These findings are not explicable in terms of the known co-factor functions of folic acid [18,19,24] or the action of methotrexate as a folic acid antagonist [10]. Inasmuch as methotrexate, which does not precipitate in tubules [9,22] was ineffective in vivo in stimu lating glycoprotein : glycosyl transferase activity, it is concluded that the enzyme changes related to folic acid administration reported here are attribu table primarily to membrane injury rather than to any direct stimulation of the transferase enzymes.…”