Thymidylate concentration in megaloblastic anaemia

Modernising the National Health and Medical Research Council

“…Our findings for cellular deoxynucleotide levels with in vitro folate deficiency contrast starkly to the in vivo normal or increased TTP (6,22) and increased dCTP content (22) of megaloblastic marrow cells. This paradoxical normal or increased cellular TTP content, despite a block in the de novo thymidylate cycle, has been postulated to reflect activated salvage pathway dTTP synthesis.…”

Haematology at the Hammersmith Hospital and Royal Postgraduate Medical School 1934–1994

“…In 1968, I became responsible for the work of this group, moved since 1966 with the rest of the department to splendid new quarters on the fourth floor of the Commonwealth Building. Here we worked on vitamin B 12 and folate inter‐relations (Lavoie et al , 1974), the DNA defect in megaloblastic anaemia (Hoffbrand & Pegg, 1972; Hoffbrand et al , 1974) setting up the first assay of the immediate DNA precursors, the deoxynucleoside triphosphates, in human cells. Tim Peters from the Department of Medicine collaborated closely in studies of vitamin B 12 and folate absorption.…”

The history of folic acid

“…Assays for the immediate DNA precursors, the deoxynucleoside triphosphates, in human cells were established for the first time. Surprisingly, the concentration of deoxythymidine triphosphate (dTTP) was not selectively lower in megaloblastic compared with normal cells even though the anti‐folate methotrexate lowered the level rapidly (Hoffbrand et al , 1974). Nevertheless, Hoffbrand and co‐workers hypothesized that the DNA defect in folate (or vitamin B 12 deficiency) arose from thymidylate starvation, suggesting that replicating segments of DNA (replicons) opened up during mitosis but remained incomplete through lack of dTTP.…”