In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models

Abstract

Sparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.

Sparsomycin Exhibits Potent Antiplasmodial Activity In Vitro and In Vivo

“…The difference between the in vitro and in vivo antiplasmodial activity of Sm possibly resulted from its toxicity and rapid metabolic clearance [ 37 , 38 ], which does not allow adequate drug levels to be reached in vivo. A difference between in vitro and in vivo results was also reported for the antitumor activity of Sm [ 22 ].…”

“…Although Sm is likely inactive when administered orally to mice [ 7 ], the reported LD 50 of the drug following i.p. administration ranged from 170 to 380 μg/kg per injection in mice and the IC 50 in some murine tumor models varied from 125 to 500 μg/kg [ 22 ]. Accordingly, in this study, mice were treated with i.p.…”

“…When the parasitemia level reached 1%, the infected mice were intraperitoneally treated with vehicle (1 × PBS) or Sm at a dose of 100 or 300 μg/kg (modified from reported IC 50 in Ref. [ 22 ]) once daily for 7 days (0–6 dpi; modified Peters’ test [ 23 ]) for P. yoelii 17XNL and 300 μg/kg once daily for 4 (0–3 dpi; Peters’ 4-day test [ 24 ]) or 7 days (0–6 dpi, [ 23 ]) for P. berghei ANKA. The survival and clinical signs of mice were monitored daily after infection.…”

Sparsomycin – a Review and Re-assessment

“…54 Broad in vivo antitumor testing revealed that 1 was weakly active or inactive, whereas deshydroxy-sparsomycin (58), n-pentyl-sparsomycin (59), and ethyl-deshydroxy-sparsomycin (60) were significantly active in the L1210 and renal cell sarcoma models. 55 Further implications that the peptidyltransferase center where 1 interacts has a hydrophobic core were demonstrated with analogs in which polar groups at the S2-Me site were inactive, whereas S2-alkyl group modification produced lipophilic derivatives with excellent activity in the L1210 leukemia assay in mice in which test/control (T/C) >125 for prolongation of life is considered active. The n-pentyl derivative 59…”

Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets

“…Amicoumacin A was recently shown to have cytotoxic effects on breast cancer and lung cancer cells, while pactamycin had a cytostatic antitumorigenic effect on head and neck squamous cell carcinomas as a result of the induction of several cell cycle arrest regulatory proteins [ 110 , 111 ]. Sparsomycin, another cytostatic agent, also inhibited the growth of murine leukemia and renal cell carcinomas [ 112 , 113 ]. The most clinically relevant plectin ligand is omacetaxine mepesuccinate that is used to treat patients with chronic myeloid leukemia that are resistant to tyrosine kinase inhibitors [ 114 , 115 , 116 ].…”