S_ary The use of chemotherapy as a form of primary treatment for breast cancer is increasing and, as a result, more resection specimens contain tumours which have been exposed to cytotoxic drugs. We have studied the effects of chemotherapy on the tumour morphology and various biological features of breast carcinoma in a group of 35 patients. These were a group who responded to treatment in a clinical study of the use of primary chemotherapy designed to reduce tumour bulk prior to surgery. Characteristic morphological changes, temporally related to the administration of cytotoxic agents, are seen. The malignant cells become enlarged with vacuolated cytoplasm and vesicular nuclei containing prominent nucleoli; occasionally the nuclei were angular and hyperchromatic. These features are interpreted as degenerative in nature. In 15 cases sufficient material was present in the pretreatment biopsies to compare the grade of the tumours before and after chemotherapy: changes were found in six tumours. Cytotoxic drugs do not induce a consistent pattern of change in the proliferation and apoptotic indices of individual tumours, but there is a tendency to reduce proliferative activity over all the tumours as a group. It was also found that chemotherapy is capable of modifying the expression of the oncoproteins c-erbB-2 and p53 in a minority of cases of breast cancer, usually resulting in an acquisition of immunoreactive oncoprotein. It is important to be aware of these effects when studying breast carcinomas removed after chemotherapy.

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Intracellular AMP hydrolysis probably produces sufficient adenosine in ischemic heart to exert physiological activity. Because data on adenosine-producing systems in human heart are scarce, we measured 1) formation of adenosine (catabolites) in ischemic human heart slices and 2) cytoplasmic 5'-nucleotidase activity in human left ventricle. We also measured the latter in rat ventricle and cardiomyocytes. During the first 5 min of incubation, adenosine production in slices (n = 5) equaled 26 +/- 10 (SD) nmol.min-1.g wet wt-1, and total AMP content was 0.81 +/- 0.46 mM. Cytoplasmic IMP-preferring 5'-nucleotidase activity in homogenates of human heart (N-II, 167 +/- 78 mU/g, n = 23) was significantly higher than that of the AMP-preferring one (N-I, 107 +/- 61 mU/g, n = 24). Both isozymes were two to three times more active in rat heart than in human heart. Rat cardiomyocytes contained comparable amounts of the two 5'-nucleotidases. Kinetics of N-I isolated from explanted human heart displayed features similar to the enzyme from animal heart, with a Michaelis constant of 1.5 mM under maximally stimulated conditions. This form can provide the amount of adenosine found in ischemic slices. In conclusion, human heart shows lower cytosolic 5'-nucleotidase activities than rat heart. Nevertheless, cytosolic 5'-nucleotidase activity in human heart can easily account for adenosine formation during ischemia.

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Summary Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100mg m2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 51 months and the median survival was 18j months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 Gundersen et al., 1990;Jonsson et al., 1991). The response to conventional dose doxorubicin (60-70 mg m2 per 3 weeks) and to combination regimes containing doxorubicin are of the order of 50-60% (Carmo-Pereira et Steiner et al., 1983 and many others). At high doses () 100 mg m-2 per 3 weeks) response rates of over 80% have been reported in breast cancer patients (Jones et al., 1987(Jones et al., , 1990Bronchud et al., 1989). Cyclophosphamide shows a similar, if less dramatic increase in effectiveness at increasing doses (Bramwell et al., 1983;Frei et al., 1989).The importance of drug scheduling and dose intensity on efficacy and toxicity of treatment have been increasingly appreciated. When the total dose of two regimes are equivalent, the dose intensity may be of critical importance as exemplified by the lower efficacy of 35 mg m-2 doxorubicin (q 3 weeks x 16) when compared to 70 mg m2 doxorubicin (q 3 weeks x 8) (Carmo-Pereira et al., 1987). In a randomised study comparing the effect of scheduling on treatment outcome, there was no difference bet*een the equi-dose intensive regimes of doxorubicin 25 mg M2 (weekly x 12) versus 75 mg m-2 (3 weekly x 4 (Richards et al., 1992). The relative importance of these two parameters is unknown when high dose doxorubicin is used. In a previous study by Bronchud et al. (1989) The question then arises whether reducing the dose of doxorubicin further, whilst maintaining a dose intensive schedule would result in lesser toxicity without loss of treatment efficacy. To this end we have investigated the effects of doxorubicin given at 100 mg m2 at 2 weekly intervals in 18 patients with metastatic breast cancer. The first nine patients also received 500 mg m-2 cyclophosphamide and dose acceleration up to 2000 mg m-2 was intended. The epithelial toxicity of the combination chemotherapy appeared greater than expected and in consequence the remaining nine patients were treated with doxorubicin alone.The major toxicity of this regime was expected to be myelosuppression, particularly neutropenia. Myelosuppressive effects of chemotherapy can be mitigated in part by use of recombinant haemopoietic growth factors which stimulate the proliferation and maturation of haemopoietic cells in the b...