Tumour converting enzyme

L-Asparaginase, an enzyme derived from E. coli or Erwinia carotovora, has been employed in cancer chemotherapy where its selectivity depends upon the essential requirement of some tumours for the amino acid L-asparagine. Normal tissues do not require this amino acid and thus the enzyme is administered with the intention of depleting tumour cells of asparagine by converting it to aspartic acid and ammonia. Whilst L-asparaginase showed promise in a variety of experimentally induced tumours, it is only useful in humans for the treatment of acute lymphoblastic leukaemia, although it is sometimes used for myeloid leukaemia. 

Drugs that can be used to control tumour cell proliferation inhibit a variety of enzymes, including thymidylate synthase and topoisomerase (Chapter 20). The enzyme aromatase converts a ring in a steroid to an aromatic ring. It converts, for example, adrenal steroid hormones into female sex hormones, which bind to oestrogenic receptors in the ovary or breast and increase the risk of ovarian or breast cancer. Aromatase inhibitors are used to treat patients with breast or ovarian cancers that are sensitive to oestrogen. Unfortunately, none of the inhibitors is specific for enzymes in tumour cells and they can therefore have severe side-effects (Chapter 21). 

Vitamin D is associated with biological functions, such as bone formation, immune system responses, cell defences and anti-tumour activity.615,616 Vitamin D comes in two closely related forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), and their metabolites. Both vitamin D2 and D3 occur naturally in some foods. However, vitamin D3 (63) can also be synthesized in skin cells called keratinocytes from 7-dehydrocholesterol (provitamin D 64), which undergoes a photochemical six-electron conrotatory electrocyclic ring opening at 280nm to previtamin D3 (41 see also Scheme 6.8), which spontaneously isomerizes to 63 in a thermal antarafacial hydride [l,7]-sigmatropic shift (Scheme 6.21). Both vitamin D2 and D3 are subsequently converted to active hormone 1,25-D by enzymes in several steps. The recommended daily intake of vitamin D for humans is 5 10 pg per day. For example, 15 ml of fish liver oils and 100 g of cooked salmon contain approximately 35 and 10 pg... 

Other examples follow of resistance achieved by increased production of a destructive enzyme. The treatment of acute leukaemia with cytosine arabino-side 4.13) fails in proportion as malignant cells with a higher concentration of cytosine deaminase appear (Steuart and Burke, 1971). Acquisition of insensitivity to 6-mercaptopurine by acute lymphocytic leukaemia cells in Man, and by murine sarcoma 180/TG, was shown to be due to an increase in alkaline phosphatase which causes degradation of the tumour-inhibiting nucleotide to which the cell converts this pro-drug (Rosman etal., 1974). 

In experimental tumours, resistance to 6-mercaptopurine is usually caused by deletion of an enzyme required to convert this pro-drug into the active molecule. The enzyme is hypoxanthine—guanine phosphoribosyltransferase (Harrap, 1976). Resistance to this drug in leukaemic patients seems to follow the same course (Rosman and Williams, 1973). 

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