N. Deshpande

Plasma concentration gradient of steroid hormones across human mammary tumours in vivo.

Abstract The paraendocrine behaviour of human breast tumours was studied in vivo. From 10 women with an established mammary tumour, blood samples were taken during mastectomy from the main internal artery of the mammary gland and from its corresponding vein. In these blood samples 10 steroid hormones (oestrogens and androgens) were estimated. All tumours investigated show a positive or negative gradient for one or more steroid hormones. The results indicate that also in vivo human breast tumours are able to modify their own endocrine environment by a wide variety of metabolic conversions. With the exception of Adione we cannot conclude whether these metabolic conversions are of significance for the development of mammary tumours because of the inconsistent pattern in the changes of hormone levels between arterial and venous blood.

Tumour enzymes and prognosis in human breast cancer

Abstract The activities of 6-phosphogluconate dehydrogenase, phosphofructokinase and α-glycerolphosphate dehydrogenase were measured in primary carcinomas from a series of 333 patients with carcinoma of the breast and the usefulness of these estimations as additional prognostic parameters was evaluated. The patients in the series were followed for up to 50 months during which time 84 patients have developed recurrent disease. Life table analyses of the results showed that the probability of remaining free from recurrence was greater in women whose carcinomas had low activities of 6-phosphogluconate dehydrogenase and phosphofructokinase and high α-glycerolphosphate dehydrogenase activity. Low ratios of α-glycerolphosphate dehydrogenase to 6-phosphogluconate dehydrogenase were associated with a considerably increased risk of recurrence. These findings further indicate the usefulness of such assays as an aid to prognosis.

Oestriol in human breast tumours

Abstract The role of oestriol in blocking the accumulation of oestradiol-17β by human breast tumours was investigated in patients with primary breast cancer. It was observed that oestriol is accumulated and retained by these tumours. However, pre-treatment of patients with 0.5 mg of the compound every 4 h for one and 3 days prior to mastectomy failed to reduce the accumulation of oestradiol indicating that, clinically oestriol may not be effective in inhibiting the action of oestradiol. The significance of the finding is discussed.

Hormonal imbalance in breast cancer.

Abstract The relation of the adrenal steroidogenesis in the responsiveness of patients with metastatic breast cancer to endocrine ablation was investigated using both perfusion of the gland in situ, and continuous peripheral infusion of pregnenolone. The results obtained by both techniques indicated that unresponsive patients converted a smaller proportion of pregnenolone to androgens relative to cortisol. Furthermore, the differences in the relative rates of synthesis were not due to abnormalities in the production or metabolic clearance rate of the precursor. The ability of the primary breast tumours to synthesize hormones and thus become independent of the hormonal environment was investigated by both the perfusion of the human breast in situ and the incubation of the neoplasm in vitro. It was observed that the tumours were capable of converting pregnenolone and dehydroepiandrosterone to progesterone and androstenedione, respectively. Inability of these neoplasms to convert cholesterol to pregnenolone indicates that the tumours rely on a continuous supply of precursors.

The effects of the administration of tamoxifen, ethynyloestradiol, and prednisolone on the activities of certain enzymes of carbohydrate metabolism in primary human breast carcinomas in vivo

Postmenopausal patients with primary breast cancer were treated with tamoxifen, ethynyloestradiol or prednisolone for up to 12 days before mastectomy and the effects of pretreatments with these drugs on the activities of phosphofructokinase (PFK), 6-phosphogluconate dehydrogenase (6PGDH) and alpha-glycerolphosphate dehydrogenase (alpha-GPDH) in the carcinomas were compared with age, stage and menopausal status matched untreated controls. The administration of tamoxifen or prednisolone resulted in a significant increase in the activity of alpha-GPDH and the alpha-GPDH/6PGDH ratio, whereas ethynyl-oestradiol treatment produced a significant decrease in the activity of the enzyme and the ratio. When tamoxifen and ethynyl-oestradiol were administered together, it was found that tamoxifen failed to reverse the oestrogen-induced reduction in the activity of alpha-GPDH. Since increased activity of the enzyme or a higher alpha-GPDH/6PGDH ratio are associated with a lower risk of recurrence (Deshpande et al., 1981), it is postulated that the beneficial effects of tamoxifen or prednisolone in terms of prolongation of the relapse free interval might be mediated via alterations in the activity of alpha-GPDH in micrometastases. The activities of PFK and 6PGDH remained unaffected by these treatments.

Corticotropin and Morphine Interaction in the Regulation of Phosphofructokinase Activity in Rat Mammary Gland

The roles of corticotropin and morphine in the regulation of phosphofructokinase (PFK) activity in rat mammary glands were investigated by the administration of corticotropin, morphine and dexamethasone. Corticotropin increased the activity of PFK in the mammary glands of intact and hypophysectomised animals but was without any effect in tissues from ovariectomised and adrenalectomised animals. Morphine administration resulted in a significant decrease in the enzymes activity in intact animals only. A combined dose of corticotropin and morphine significantly reduced the corticotropin-induced increase in the activity in both intact and hypophysectomised animals. Dexamethasone treatment resulted in a significant increase in the activity in hypophysectomised and ovariectomised plus adrenalectomised animals and morphine was able to reduce the glucocorticoid-induced rise. It is postulated that endogenous opioids might be playing a dual role in the regulation of glycolysis by inhibiting the release of corticotropin and regulating the action of glucocorticoids at the cellular level in the mammary gland.

The activity of phosphohexose isomerase in primary breast carcinomas and response to chemotherapy in patients with metastatic disease

SummaryThe activity of phosphohexose isomerase [PHI] was measured in 48 primary carcinomas from patients with breast cancer, and its usefulness as a predictor of response to cytotoxic drugs at the metastatic stage was evaluated. There was a statistically significant difference in the activity of PHI between responders and non-responders to these treatments. These preliminary findings are currently being evaluated in an extended series.

Prolactin, Thyrotrophin Interaction in the Regulation of Glucose-6-Phosphate Dehydrogenase and 6-Phosphogluconate Dehydrogenase Activities in Rat Mammary Glands

The roles of prolactin and thyrotrophin (TSH) in the regulation of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) activities in rat mammary glands were investigated by the administration of thyroid hormone-releasing hormone (TRH), bromocriptine, prolactin, TSH and triiodo-1-thyronine (T(3)). TRH failed to induce changes in the activities of these enzymes in glands from intact animals but the releasing hormone significantly increased the activities of both the enzymes in the glands of ovariectomized and adrenalectomized animals. Bromocriptine administration had no effect on the activities in both, intact and ovariectomized-adrenalectomized animals. Administration of ovine prolactin to hypophysectomized rats did not affect the activities of these enzymes. On the other hand treatment with TSH resulted in significant increases in the activities. On the other hand treatment with TSH resulted in significant increases in the activities. Similarly, administration of T(3) to these animals resulted in changes similar to those observed after TSH administration. Combined administration of prolactin and TSH showed that prolactin is capable of partially inhibiting the TSH-induced increases. It is concluded that TSH is involved in the channelling of substrates into the pathways of nucleic acid synthesis and prolactin probably plays a regulatory role in this process.

The effects of oestradiol-17β, provera and tamoxifen on glucose metabolism in mammary gland, liver and muscle of the rat

Abstract The activities of seven enzymes associated with glucose metabolism were measured in muscle, liver and mammary glands of intact, castrated and castrated rats treated with progesterone, oestradiol-17β or Tamoxifen. The following differences were observed: I. Castration significantly reduces the activities of G6PDH and PGM in the mammary glands whereas it increases total protein content of the tissue. Administration of progesterone or oestradiol failed to alter these castration-induced changes. Tamoxifen treatment reduces the castration induced rise in total protein and PGM activity: 2. Castration induces a significant reduction in the activity of 6PGDH and an increase in the activity of PHI in liver. Administration of oestradiol to castrated animals increases the activity of 6PGDH to the levels found in intact animals. Tamoxifen treatment showed a significant decrease in the activities of G6PDH, 6PGDH and PHI: 3. Neither castration nor any of the subsequent treatments affected glucose metabolism in muscle.

Effect of tamoxifen pre-treatment on the retention of tritiated oestradiol and 5α-dihydrotestosterone and on glucose metabolism in human breast carcinomas

Abstract The effect of pre-treatment with tamoxifen glucose metabolism and retention of injected oestradiol- 17 β and 5 α-dihydrotestosterone by human breast carcinomas were studied in patients undergoing mastectomy. The following effects were observed: 1 . The pretreatment reduced retention of oestradiol- 17 β whereas a small but statistically significant rise in 5 α-dihydrotestosterone accumulation was observed. 2 . There was an increase in both phosphofructokinase (PFK) and glucose- 6 -phosphate dehydrogenase (G 6 PDH) activities in tumours from treated patients whereas α-glycerolphosphate dehydrogenase (α-GPDH) activity was significantly reduced in the same tumours. 3 . The significance of these findings is discussed and it is argued that these changes in carbohydrate metabolism may not be due to the blocking of hormone receptors.