LABORATORY STUDIES AND CLINICAL TRIALS OF CHEMICAL RADIO-SENSITIZERS 



(2) in Storage, detoxication or elimination organs. There is a close correlation between 

 the capacity of the cells to absorb Synkavit, and the rate of renewal of deoxyribo- 

 nucleic acids. Further, the retention of the product is greater when the proliferation 

 is more intense. 



It has been clearly shown that Synkavit does not provoke any important morpho- 

 logical lesions in mitosis. It is a weak antimitotic. By histophotometric measure- 

 ments of fibroblast nuclei cultivated in vitro and stained by the Feulgen reagent, we 

 have established that Synkavit decreases the proportion of cells containing high con- 

 centration of deoxyribonucleic acid (pre-prophasic nuclei). 



With the concentrations we have used the proliferation of the cultures is not 

 hindered. The observed effect is thus not bound to a decrease in the number of 

 mitosis, but rather to change of the time of synthesis of the deoxyribonucleic acid, 

 leading to a delay of prophase. Our research shows that the quantity of Synkavit 

 necessary to obtain this effect is extremely low. This corroborates and reinforces 

 the idea that the basic molecule of Synkavit remains fixed in the cell and intervenes 

 in the metabolism of the deoxyribonucleic acid. 



The damage caused to the fibroblast cultures immersed in Synkavit solutions 

 containing proteins is only half that found in solutions (Tyrode) that do not con- 

 tain any proteins. On the other hand, exposure of cultures for 50 minutes to Syn- 

 kavit in Tyrode solution shows damages equal to that caused by Synkavit directly 

 introduced in the culture medium ; in other words, with equal concentrations, the 

 effect of Synkavit develops in 50 minutes in Tyrode and in 48 hours in plasma. 

 Other experiments (cultures treated with Synkavit compared with non-treated 

 cultures, influence of the number, the duration and the volume of the wash-liquid 

 after exposure of the cultures to Synkavit) show that Synkavit is for the greatest 

 part adsorbed on the proteins or on the cellular membranes.* 



These data help to explain the important difference in the therapeutic eff^ect 

 obtained by administering Synkavit by the intramuscular or intravenous route. 

 The combination ' Synkavit-proteins ' cannot be effected instantaneously and depends 

 on the local concentration of Synkavit. When the latter is introduced into the 

 muscular tissues, it remains there longer and at a higher concentration than when it 

 is introduced in the blood-stream and therefore cannot reach distant organs in 

 sufficient concentration. 



B. JoLLES : Having used Synkavit in over two hundred patients with advanced 

 malignant disease undergoing radiotherapy, and noted the beneficial effects of the 

 administration of this compound as a coadjuvant of radiotherapy, I should like to 

 draw attention to the formula of Karnofsky mentioned by Mitchell in view of the 

 fact that often, particularly in the case of patients with carcinoma of the lung, the 

 results assessed on the basis of survival times do not give the true picture of the 

 efficacy of the treatment. This is often better assessed instead on the basis of criteria 

 concerning comfort and relief of symptoms which accrue from a particular method 

 of treatment. 



J. O. Laws and B. Jolles : Amongst the attempts to improve the results of the 

 radiotherapy of some types of cancer, especially those in which results are unsatis- 

 factory, by the ancillary use of chemical agents designed to act as radio-sensitizers, 

 the work of MiTCHELLf (1948) has been most consistently and thoroughly pursued. 

 After many clinical trials Mitchell J (1952) has shown that the administration of 

 tetrasodium 2-methyl-l : 4-naphthohydroquinone diphosphate (synthetic vitamin K 

 derivative, Synkavit, Roche) to patients with advanced malignant disease improves 



* Richard, M., Peguiron, L. and Neukomm, S. Arch, internal. Pharmacodyn. TMrapie, in 

 press. 



t Mitchell, J. S. Brit. J. Cancer, 1948. 2 351-358. 



+ Mitchell, J. S. Brit. Empire Cancer Camp. 30th Ann. Rep. London, 1952, p. 239. 



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