538

maternal blood loss, or fetal wellbeing.2O In addition, self-administered isoflurane proved superior to ’Entonox’ (50%N2O, 50% O2) as an analgesic in the first stage oflabour. 21Although isoflurane may appear to be better in many ways

than other potent volatile anaesthetics, it has at present twolarge drawbacks. It is far more expensive than existing agents,and if introduced widely into anaesthetic practice mightnecessitate a change to low-flow breathing systems or closedcircuit anaesthesia to limit costs. Also, clinical experiencewith isoflurane is limited and some noxious effect mayemerge with wider use. On present evidence, isoflurane islikely to be much used in anaesthetic care.

BONE MARROW UNDER ATTACK

THE immediate effects on the haemopoietic marrow ofcytotoxic drugs and radiation therapy are well known;indeed, they constitute a limiting factor in devisingtherapeutic protocols for malignant disease, unless theprotocol includes bone-marrow transplantation. The marrowhas remarkable functional reserves, however, and often seemsto recover completely-at least as judged by peripheral bloodcounts-even after repeated episodes of myelosuppression.Nevertheless, there is evidence that it does not escape entirelyunscathed after intensive therapy for malignant disease,whether this is intrinsic or extrinsic to the marrow. Inaddition to their leukaemogenic potential, radiation and

cytotoxic drugs can produce permanent changes in the

proliferative behaviour of the marrow. These effects may beconsidered analogous to the structural and functional defectswhich occur in the lung, heart,2 and reproductive organs3after cancer and leukaemia therapy, sometimes with

devastating clinical results.In a series of in-vivo experiments, Knospe and Crosby4,5

demonstrated the important relation between the marrowstem-cell ("seed") and its specialised vascular sinusoidalmatrix ("soil"): using graduated doses of radiation they wereable to distinguish different effects on the two elements,which might or might not be reversible. Another experimentdemonstrated that, when marrow is transplanted ectopically,haemopoiesis occurs only after a stromal matrix has

developed.6 More recently in-vitro culture techniques haveshown that marrow stroma includes, in addition to vascularendothelial cells, other constituents such as epithelial cells,macrophages, fat cells, and a cell called by Dexter the"blanket cell".’ Collectively, these constituents form thehaemopoietic inductive environment; they and their

biosynthetic products are believed to play an important role

20 Warren TM, Datta S, Ostheimer GW, et al. Comparison of the maternal and neonataleffects of halothane, enflurane and isoflurane for cesarian delivery. Anesth Analg1983, 62: 516-20.

21. McLeod DD, Ramayya GP, Tunstall ME. Self administered isoflurane in labour—acomparative study with entonox. Anaesthesia 1985; 40: 424-26

1. Sostmann HD, Mattay RA, Putman CE. Cytotoxic drug-induced lung disease. Am JMed 1977; 62: 608-13.

2. Bonnadonna G, Montfardini S. Cardiac toxicity due to daunorubicin. Lancet 1969; i:837.

3. Shalet SM. Effect of cancer chemotherapy on gonadal function of patients. CancerTreatment Rev 1980; 7: 141.

4. Knospe WH, Bloom J, Crosby WH. Dose dependent long-term changes in the rat bonemarrow with particular emphasis upon vascular and stromal defects. Blood 1966;28: 398-415.

5. Knospe WH, Crosby WH. Aplastic anaemia: A disorder of the bone marrow sinusoidalmicro-circulation rather than stem-cell failure. Lancet 1971; i. 20-23.

6. Tavassoli M, Crosby WH. Transplantation of marrow to extramedullary sites. Science1968; 161: 54-56

7. Dexter TM. Stromal cell associated haemopoiesis. J Cell Physiol 1982; suppl I. 87-94.

in promoting and regulating haemopoiesis.8 Any of thesecells-the seed or the soil-might be damaged by cytotoxicdrugs or X-irradiation.Testa and her colleagues9 have recently reviewed the

evidence that cytotoxic agents may inflict irreversible damageon the marrow. Much of this information comes from

experiments in mice-for example, if a mouse is givenrepeated doses of busulphan over several weeks, the numberof stem cells (CFU-S) in its marrow may fall to 1% of thestarting value, even though the blood count does not

changes Marrow hypoplasia may develop later, either

spontaneously or when the animal is exposed to some

otherwise trivial insult;" its residual stem-cells have a greatlyreduced capacity for self-renewal and are comparativelyineffective in transplantation experiments. Small doses ofradiation have a similar effect-here the brunt of the damagefalls on the stem-cell. In contrast, other drugs, such as

cyclophosphamide, seem to damage the soil, perhaps to agreater extent than the stem-cell. 12

In man, quantitative defects in bone-marrow function, asindicated by low numbers of granulocyte/macrophageprecursors (GM-CFC) in culture, have been found after long-term remission of acute myeloblastic leukaemia9 and acutelymphoblastic leukaemia.13 Similar defects have also beenfound after chemotherapy for diseases not intrinsic to themarrow, such as non-Hodgkin lymphoma 14 and carcinoma ofthe breast,9 and after radiation therapy for Hodgkin’sdisease.lS,16 Although clinical evidence of marrow depressionis unusual at this stage, the patient’s tolerance of furthercourses of therapy may be impaired. Testa’s group speculatethat this functional hypoplasia, perhaps exacerbated by theimmunosuppressive effects of the original therapy, mayfacilitate the emergence of a leukaemic clone. Many patientswith secondary (therapy-linked) leukaemia are known to passthrough a prodromal phase of pancytopenia, and the marrowmay then be morphologically hypocellular.’ 7,18 Moreover,the aplasia seen in irradiated mice may itself be a pre-leukaemic syndrome.More information is needed on the state of both the marrow

seed and its soil after intensive chemotherapy and irradiation;this must include patients in whom these treatments are usedin the context of bone-marrow transplantation.

8. Singer JW, Keating A, Wright TN The human haematopoietic environment. In:Hoffbrand AV, ed. Recent advances in haematology, No 4. Edinburgh: ChurchillLivingstone, 1985: 1-24.

9. Testa NG, Hendry JH, Molineux G. Long term bone marrow damage in experimentalsystems and in patients after radiation or chemotherapy. Anticancer Res 1985; 5:101-10.

10. Morley A, Trainor K, Black J. A primary stem cell lesion in experimental chronichypoplastic marrow failure. Blood 1975; 45: 681-88.

11. Morley A, Blake J. An animal model of chronic aplastic marrow failure I. Late marrowfailure after busulphan. Blood 1974; 44: 49-56.

12. Molineux G, Testa NG. Long-term persistent damage to the bone marrow ofcyclophosphamide-treated mice Exp Hemat 11 1983; suppl 14. 130.

13. Haworth C, Morris-Jones PH, Testa NG. Long term bone marrow damage in childrentreated for ALL: Evidence from in vitro colony assays (GM-CFC and CFU-F) Br JCancer 1982; 46: 918-23.

14. Hartmann O, Parmentier C, Lamede J. Sequential studies of bone marrow CFC inchildren treated by chemotherapy for NHL. Nouv Rev Franc Hematol 1978; 21:239-41.

15. Morardet N, Parmentier C, Hayat M, Charbord P. Effects of radiotherapy on the bonemarrow granulocytic progenitor cells (CFU-C) of patients with malignantlymphomas. Long term effects. Int J Rad Oncol Biol Phys 1978; 4: 853-57.

16. Rubin P, Landman S, Mayer E, Keller B, Ciccio S. Bone marrow regeneration andextension after extended field irradiation in Hodgkin’s disease. Cancer 1973; 32:699-711.

17. Pedersen J, Bjergaard D, Philip NT, Peedersen K, Jensen KH, Svejgaard A, Jensen G,Nissen NI. Acute non-lymphocytic leukemia, preleukemia and acute

myeloproliferative syndrome secondary to treatment of other malignant diseases. II.Cancer 1984; 54: 452-62.

18. Galton DAG. The myelodysplastic syndromes. Clin Lab Haematol 1984; 6: 99-112.