VOL. 12 (1953) EFFECTS OF INSULIN ON MELANOMA . 343 



relative inability of adult brain to maintain vigorous phosphorylation of glucose under 

 anaerobic conditions (see Meyerhof and Wilson^^-^*), an ability much more inherent 

 in tissues adapted to a more anaerobic environment as e.g., embryonic tissues and 

 tumors. In the present study we were able to raise the (^coa °^ brain to the melanoma 

 level, but only following addition of high levels of magnesium and phenol. 



Insulin is of peculiar interest to the cancer problem because of its role (direct or 

 indirect) in the stimulation of glycolysis'^. Whether this stimulation results from action 

 on an intracellular enzyme or inhibitor'^ or occurs through a mere speeding up of entry 

 of glucose into the celP^'^"* cannot be fully decided at present. The work of Ryer^^, in 

 which insulin and/or thyroxine was administered in vivo to rabbits bearing the Brown- 

 Pearce epithelioma, shows that tumor metabolism can be markedly affected by insulin 

 injections. Both respiration and glycolysis were increased in the liver and tumor tissues 

 which were subsequently measured in vitro. 



In the present study, insulin was administered only after the tissues were placed 

 in the respirometer vessel so that any metabolic changes noted must have been due to 

 the immediate action of the hormone. Most investigators have measured insulin action 

 on excised tissues in terms of glucose disappearance and glycogen formation although 

 lactic acid formation and respiratory CO 2 (from labeled glucose) have also been followed 

 [cf. '^' '^' ^^). Our interest has been primarily in determining the effect of insulin on over-all 

 metabolism, particularly anaerobic and aerobic acid formation. While the results are 

 more or less in line with those of other investigators (who used normal instead of 

 malignant tissues) certain differences do occur. 



Balmain et al.^, and Hills et al.^^, have reported that insulin in vitro enhances the 

 R.Q. of lactating mammary gland tissues of rats. This effect, which seems to be due to 

 acceleration of fatty acid synthesis, did not occur in a phosphate medium and appeared 

 in bicarbonate medium only in the presence of acetate and glucose. Under the latter 

 conditions an increased 0^ uptake also occurred. We observed marked enhancement of 

 R.Q. in melanoma in both Hank-Simms and Krebs-Ringer-bicarbonate media as the 

 result of treatment with both low-zinc, and crystalline zinc-insulin. The response, 

 however, was variable. In our experiments, glucose was the only added substrate, and 

 the reasons for this variability are not clear. Unlike the results with normal tissues, we 

 have never obtained an insulin-induced increase in the Qq^ of melanoma. In spite of this, 

 insulin frequently increased the absolute Pasteur effect. These partly atypical results 

 with tumor may be related to the well-known respiratory defect in oxidative reserve 

 characteristic of malignancies generally^''. At this point we wish to comment, somewhat 

 parenthetically, on the question of this respiratory defect in tumor cells. 



Warburg suggested many years ago^^ that "the aerobic glycolysis of the tumor 

 cell is derived in any case from a disturbance of the respiration". Although certain 

 tumors have relatively high oxidative quotients, aerobic glycolysis is present if there 

 is an adequate supply of glucose {cf. Burk^). In such cases, from a relative standpoint, the 

 respiration is certainly low in relation to the glycolytic capacity. 



The role of mitochondria in mediating the oxidative processes of cellular metabolism 

 has become increasingly clear since the original discovery by Warburg^' that the 

 Atmungsferment, and other associated enzymes, are carried on the cytoplasmic parti- 

 culates. Recent work'" has indicated that mitochondria may also play a more active role 

 in glycolysis than had been generally accepted. Furthermore, these sub-cellular organelles 

 have been shown to possess extra-nuclear hereditary factors which through their 



References p. 346. 



