THE SELECTIVE INDUCTION OF CELLULAR DAMAGE WITHIN NEOPLASIA IN SITU; A PUTATIVE ROLE FOR SYMPATHOMIMETIC AGENTS

G. R. N. JONES, Institut fiir Toxikologie der Universitiit Tiibingen, 7400 Tiibingen 1, Wilhehnstrasse 56, West Germany.

SUMMARY

Cancerous cells can be selectively injured within a host by various means. The effects generally appear to be manifested indirectly, and are consistent with the concept that uptake from the plasma of non-ester&d fatty acids (NEFAs) by malignant tissue leads to an increase in uncoupling of oxidative phosphorylation. Certain lipolytic agents are already known to cause selective damage to cancerous growths in situ. The employment of appropriate sympathomimetic agents to accentuate the nocturnal rise in plasma NEFA concentrations may permit the management and control of a variety of human neoplasia.

INTRODUCTION Despite its frequent lethality, cancer is a disease that may

show susceptibility to palliative and, though much more rarely, to curative measures other than surgical interven- tion. In the human, the palliatives include exposure to radiation (1) and administration of cytotoxic drugs (2,3). In animals, the injection of preparations of endotoxin from Gram-negative organisms is one of the most effective means of producing selective damage within neoplastic cells in situ (4). In the S37 mouse sarcoma, oedema and haemor- rhage develop at 2 and 5 hours respectively after endotoxin administration to the host; later, widespread necrosis occurs within the tumour (5). Although early successes have been reported, in the human by uncontrolled or even accidental means bordering on the hazardous (see (6) for review), careful administration of purified endotoxin was sometimes without effect, and on other occasions elicited only tempor- ary improvements (5,7).

Attention has been -drawn recently to the indirectness of certain of these injurious effects (8). With regard to radiation, for example, radium needles were much more successful in treating human breast cancer when set into the healthy tissue surrounding the growth than when placed actually in the tumours themselves (9). In addition, when murine mammary cancers were excised after in situ X-irradiation normally sufficient to inflict extensive and lasting injury upon the growths, and when small pieces from the irradiated edges were transplanted to a non- irradiated site in the same animal, normal growth occurred in 79% of the cases (10). With regard to endotoxin, cells from a rat sarcoma and a rat carcinoma were insensitive in tissue culture to up to 5000 times the amount of endotoxin necessary to produce haemorrhagic necrosis in the same tumours in situ (11). Also, when endotoxin labelled with i3’I was injected into mice bearing the S37 sarcoma, uptake of 13’1 by the growth was negligible, even though the tumour-necrotising activity of the preparation had not been altered significantly by labelling (5).

THE RELEVANCE OF SHOCK Virtually all the procedures by which injury may be

selectively inflicted upon malignant growths can, when taken to extremes, precipitate a state of shock. In this con- dition it appears that NEFAs, after uptake from plasma albumin by target organs such as liver, depress oxidative metabolism by increasing the ongoing inhibition of the adenine nucleotide translocase through the agency of coenzyme A derivatives (( 12); also G. R. N. Jones and R. Krlmer, in preparation). Alternatively, uptake of fatty acids by tumours not isolated from the plasma by the blood-brain barrier might set off a train of events involving an un- coupling of oxidative phosphorylation (8), thereby culminat- ting in selective cellular damage. In this connection the exponential increase in the rate of palmitic acid removal from an albumin vehicle by Ehrlich ascites cells as the fatty acid concentration was arithmetically increased (13) may be relevant; in other words, in this particular tumour a doubling in the NEFA concentration could theoretically result in a tenfold increase in the rate of NEFA uptake. Studies in which mice bearing the Cracker sarcoma (Sl80) were injected with endotoxin in vivo, followed by the isolation of tumour mitochondria, showed that oxidative phosphorylation became almost totally uncoupled within 30 min. of endotoxin injection into the host animal (( 14); also G. R. N. Jones, in preparation). The insubstantial level of coupling persisted to 4 hr, but was completely abolished by 8 hr. Moreover, the capacity of bovine serum albumin to restore coupling (15), which was impressive in tumour mitochondria from saline-injected control animals,

gradually fell over the 8 hr period of study, to a final value only one sixth of the original,

LIPOLYSIS AND TUMOUR DAMAGE On the basis of the foregoing concept, substances with

lipolytic activity might be expected to injure cancerous growths in situ. Epinephrine ( 16,17,18) norepinephrine ( 18) and vasopressin (18) have already been shown to possess

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this property, as do the sympathomimetic agents ampheta- mine and isoproterenol (18). Although the suggestion has been made (19) that the injurious effects of endotoxin on transplanted tumours are mediated by changes in the blood supply leading to stasis within the capillaries serving the tumour, and hence anoxia, similar damage did not ensue within striated muscle in the host animals, even though the same kinds of circulatory alterations were seen both in tumour and in muscle (19). Moreover, the various sub- stances found to be active against tumours in the later study (18) produced no consistent effect on the arterial blood pressure, while the majority of a total of twenty-seven other compounds devoid of harmful properties tended to lower blood pressure (18).

Plasma NEFA concentrations are subject to various endocrine influences (20) as well as to starvation (21,22), and exhibit circadian rhythms in man (23,24). Although one of these studies (23) was conducted with psychiatric patients and no mention was made of medications, both groups reported a substantial rise in NEFA levels at night (23,24). Other sympathomimetic substances have been developed for various purposes since the tumour-damaging effects of amphetamine and isoproterenol were reported (18). Some of these, such as the anorexogenic agent fenfluramine (25), are known to raise plasma NEFA con- centrations in man, and might find use in boosting and maintaining the nocturnal increase, provided that unwanted side-effects can be kept to a minimum. The finding that sarcomas tend to be more vulnerable to injury from bacterial agencies than carcinomas (6) may be reflected by a similar differential susceptibility to sympathomimetic compounds. The lipotropic response of a host to a tumour has already been discussed in terms of a naturally-occurring defence mechanism against neoplastic growth (see (8) for references). The imposition of a dietary regimen that attempts to correct the cachexia frequently seen in cancer patients while accentuating the nightly rise in plasma NEFA concentrations may prove to be a useful auxiliary.

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