II PREPROPHASIC INHIBITION 933 



It is known that the nucleoside, 2,6-diamino-9-[i-D-ribofuranosylpurine, which 

 inhibits mitosis in mouse tissue cultures at 2 mM (Biesele, Berger, Clarke and 

 Weiss, 1952), is enzymatically phosphorylated to 2-aminoadenosine triphosphate 

 (Kornberg and Pricer, 1951). In the intact movise, 2,6-diaminopurine-2-''*C is 

 rapidly incorporated into a phosphorylated derivative of the riboside, probably 

 also 2-aminoadenosine triphosphate (Wheeler and Skipper, 1953). 



2j6-Diaminopiu'ine is also known to affect adversely the de novo synthesis of 

 nucleic acid purine. It blocks conversion of folic acid to citrovorum factor (Doctor 

 and Trunnell, 1955) and inhibits the incorporation into nucleic acid of labeled 

 formate (Skipper, Mitchell, Bennett, Newton, Simpson and Eidson, 1951), 

 4-amino-5-imidazolecarboxamide (Miller and Warren, 1953), and radiophos- 

 phate (Visser, 1955). 



Several adenine analogues with changes at the 2-position act somewhat like 

 2,6-diaminopurine on mouse tissue cultures. Sarcoma 180 cells are damaged 

 selectively, and few mitoses occur in concentrations of 0.05 mMof 2-chloroadenine 

 or higher (Biesele, Berger, Clarke and Weiss, 1952) or 2-azaadenine (Biesele, 

 1952). Both these compounds differ from 2,6-diaminopurine and adenine in their 

 failure to break chromosomes. 



Another adenine analogue that selectively inhibits mitosis in certain neoplastic 

 cells is 4-aminopyrazolo-(3,4-fl')pyrimidine (Hsu, Robins and Cheng, 1956). 

 This agent inhibits mitoses or renders them pathological in cultures of some neo- 

 plasms, including the human cancer strain HeLa, and causes pyknosis of resting 

 nuclei. It appears to have little effect on the normal mouse and human cells tested. 



Unsubstituted purine at about o.i m.\/ differentially suppresses mitosis in cells 

 of mouse sarcoma 180 in culture (Biesele, Slautterback and Margolis, 1955). 

 Adenine reverses the mitotic inhibition more readily in the skin cells than in the 

 sarcoma cells. Various adenine nucleotides also show blocking ability, especially 

 for the embryonic mouse skin cells. 



The 6-substituted purines include some agents that inhibit the growth of certain 

 neoplasms (Clarke, Philips, Sternberg, Stock, Elion and Hitchings, 1953). Some 

 also affect the growth of certain normal tissues. Tentacle-regeneration in hydra, 

 for example, can be inhibited with 6-(phenylalkyl) aminopurines (Ham, Eakin, 

 Skinner, and Shive, 1956). 



Both 6-mercaptopurine and 6-chloropurine at concentrations of i xnM and 

 higher cause a differential partial inhibition of cell division in cultures of mouse 

 sarcoma 180 (Biesele, 1954c, 1957). Much the same effect is produced by 6- 

 methylmercaptopurine. 6-Methylpurine is far more toxic and suppresses naitosis 

 completely at 0.0 1 mAf. Thioguanine is of intermediate toxicity but causes no 

 differential suppression of mitosis of sarcoma cell in culture (Biesele, ig58a). 



Several other 6-substituted purines have been studied. One of these, 6-furfuryl- 

 aminopurine or kinetin, increases mitotic rate greatly in plant tissue cultures 

 (Miller, Skoog, Okumura, Von Saltza and Strong, 1955), but it has little effect 

 on animal cells. Lettre and Endo (1956) found kinetin neither to stimulate nor 

 to inhibit normal and malignant animal and human cells in culture, but the deriv- 

 ative, 6-p-indolylethylaminopurine, was found to inhibit mitosis at concentra- 

 tions of 10 [i-g/ml and above. Biesele (1957) found that kinetin at the high con- 



Literature p. g^y 



