Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The combination of Ethyldeshydroxy-Sparsomycin (EdSm) with cisdiamminedichloroplatinum(II) (CDDP) caused significant antitumour activity against murine L1210 leukemia. Although single drug treatment by cisplatin generated some cures, all schedules of combined treatment, using nontoxic doses of EdSm (5mg/kg) and cisplatin (3 mg/kg), resulted in the cure of 4 to 6 mice in each group consisting of 6 mice. No differences in antitumour activity were observed between pretreatment, simultaneous treatment or posttreatment of cisplatin with EdSm. Increasing the number of tumour cells implanted i.p. diminished the antitumour effect of both EdSm as well as CDDP, but not for the drug combination. Changing the route of administration from i.p. to i.v. for one of the drugs out of the combination resulted in loss of antitumour activity.
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PMID:Potentiation of cisplatin antitumour activity by Ethyldeshydroxy-Sparsomycin in L1210 leukemia. 156 64

The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs mitozolomide is one of the most effective compounds in these tumors. These data indicate that mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow. 225 73

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.
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PMID:In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models. 322 41

Sparsomycin is a cytotoxic drug exhibiting a broad spectrum of in vitro activity against murine tumors and many tumor cell lines. It also appears to be a potent stimulator of the antitumor activity of cisplatin against L1210 leukemia in vivo. However, because of its toxicity, the antitumor activity of sparsomycin on murine tumors in vivo has been disappointing. The purpose of our study was to investigate the pharmacokinetics of this drug as well as the possible mechanisms that produce sparsomycin toxicity. Tests on beagle dogs revealed that about 60% of the drug is eliminated by metabolic clearance, while 40% is eliminated by the kidneys. After a single bolus injection of 0.1 mg/kg sparsomycin without narcosis, sparsomycin was eliminated with a t beta 1/2 of 0.6-0.7 h, the AUC being 0.32-0.38 mg.h.l-1, and the volume of distribution (Vd) 0.26 l/kg. In addition to being subject to glomerular filtration, sparsomycin is probably also actively excreted and actively reabsorbed by the renal tubuli. Sparsomycin itself may inhibit its active tubular excretion, thus resulting in a decrease in the drug's renal clearance and its accumulation in the plasma. Sparsomycin appeared to be toxic primarily in the liver, disturbing its function and the synthesis of plasma proteins. Two out of five dogs developed hemorrhagic diathesis due to hypofibrinogenemia and deficiency of other blood-coagulation factors. Sparsomycin was not toxic to the bone marrow.
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PMID:Pharmacokinetics and toxicology of sparsomycin in beagle dogs. 366 30