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PubMed1977

Pyrimidinylpropenamides as antitumor agents. Analogues of the antibiotic sparsomycin.

A series of pyrimidinylpropenamides 9 and their oxidation products 10 was prepared, as analogues of sparsomycin (1), for antitumor evaluation. Syntheses involved condensation of the appropriate amino alcohol 5 with acid 8. The resulting sulfides 9 were then oxidized with NaIO4 or H2O2 to sulfoxides 10. Activity was studied in lymphocytic leukemia P-338 and KB cell culture. With the exception of the n-decyl analogue, all of the deoxygenated compounds 9 were inactive regardless of the stereochemical form. In the sulfoxide series 10, those compounds prepared with an L configuration at the asymmetric carbon were also inactive. The completely racemic sulfoxides, on the other hand, displayed substantial antitumor activity (ILS = 37-61% in P-388; ED50 = 1.2-2.4 mug/ml in KB) suggesting that both the presence of a sulfoxide moiety and a D configuration at the chiral carbon atom were structural requirements for a positive antitumor response. There appeared to be a large tolerance for the group substituted at the sulfoxide moiety, however.

Animals↗
PubMed1994

Concentration and sequence dependent synergism of ethyldeshydroxy-sparsomycin in combination with antitumor agents.

The modulating effect of ethyldeshydroxy-sparsomycin (EDSM), an inhibitor of ribosomal protein synthesis, on cytostatic agents was studied on cultured B16 melanoma cells using the microculture tetrazolium test (MTT). The data were analyzed for true synergism using the combination index and the median effect principle. The extent of cytotoxic drug interaction was influenced by the duration of drug exposure, the dose ratio, as well as the treatment schedule. When drug ratios were used, synergism was observed upon pre- and post-treatment in combination with cisplatin, cytosine arabinoside (Ara-C), methotrexate (MTX) and 5-fluorouracil (5-FU). The combination of a fixed dose of EDSM was synergistic with cisplatin, Ara-C, vincristine (VCR) and MTX, in the order MTX > Ara-C > VCR > cisplatin, while the combinations with doxorubicin, 5-FU and etoposide (VP-16) were shown to be antagonistic. These results suggest that only certain drugs and treatment schedules might be worthwhile for combination studies with EDSM in vivo and indicate a role for EDSM as modifier of antitumor responses in cancer chemotherapy.

Animals↗
PubMed1995

Schedule-dependent enhancement of antitumor activity of ethyldeshydroxy-sparsomycin in combination with classical antineoplastic agents.

The efficacy of the protein synthesis inhibitor ethyldeshydroxy-sparsomycin (EDSM) as a biochemical response modifier of several antitumor agents against L1210 leukemia and B16 melanoma is described. Seven drugs with different intracellular targets were selected for this combination study. Tumor implantation and drug treatment were both i.p., and the time interval between the administration of EDSM and the cytostatic agent was varied. Our results show that in the B16 tumor model EDSM is not able to potentiate any of these drugs, whereas antagonism is seen in combination with doxo-rubicin (DX). In the L1210 tumor model, however, no loss of activity is seen for this specific combination. The effect of the combination of cytosar (Ara-C), 5-fluorouracil (5-FU) or vincristine (VCR) with EDSM in the L1210 model is strongly time interval dependent. Loss of 5-FU antitumor activity is seen when EDSM is given 3 or 24 h after 5-FU; however, no effect is observed when EDSM is given 6 h after 5-FU. Enhancement of the 5-FU activity is not noticed. The VCR activity is potentiated when EDSM is given at least 6 h after VCR administration, which increases the antitumor response from 32 to > 60 days and the percentage survivors from 33 to 83% (p = 0.04). In combination with Ara-C, potentiation of antitumor activity is seen only when EDSM is given 24 h after Ara-C, which increases the antitumor response from 32 to > 55 days and the percentage survivors from 11 to 50% (p = 0.008). No modulatory effects are found when EDSM is combined with carmustine or DX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The effect of ethyldeshydroxy-sparsomycin and cisplatin on the intracellular glutathione level and glutathione S-transferase activity.

Ethyldeshydroxy-sparsomycin (EdSm) is a ribosomal protein synthesis inhibitor which synergistically enhances the antitumor activity of cisplatin against L1210 leukemia in vivo. Because cellular glutathione (GSH) and glutathione S-transferases (GST) are reported to interfere with the antitumor activity of cisplatin, we analyzed the effect of EdSm and cisplatin on GSH and GST activity in selected tumor cells. For this purpose we used three murine leukemia tumors with different sensitivities towards EdSm and cisplatin: L1210-WT, sensitive to both drugs, L1210-Sm, resistant to EdSm, and L1210-CDDP, resistant to cisplatin. No significant differences were detectable between these three cell lines regarding the population doubling time, the cell size, and the cellular level of protein and glutathione. Neither of the resistant L1210 subclones showed P-glycoprotein expression. Drug exposure, however, changed the intracellular dynamics. Exposure to EdSm strongly decreased the amount of cellular protein, decreased the overall GST activity and led to GSH depletion, whereas exposure to cisplatin induced a rise in the amount of protein, in GSH, and in the total GST activity. These effects are dose-dependent and correlate well with the sensitivity of the tumor cells for EdSm or cisplatin. In addition, exposure to EdSm lowered the V(max) of GST in L1210-WT and L1210-Sm; however, in L1210-CDDP both the V(max) and the K(m) were increased. That this was not a direct effect of EdSm on GST was shown in a cell-free system, where EdSm did not influence the GST activity nor could it act as a substrate for GST. Our results suggest that the synergistic combination of EdSm and cisplatin might be explained by EdSm switching off the cellular detoxification mechanism for cisplatin, i.e. by inhibition of de novo synthesis and subsequent depletion of GSH and GST.

Animals↗
PubMed2003

Catalysis of ribosomal translocation by sparsomycin.

During protein synthesis, transfer RNAs (tRNAs) are translocated from the aminoacyl to peptidyl to exit sites of the ribosome, coupled to the movement of messenger RNA (mRNA), in a reaction catalyzed by elongation factor G (EF-G) and guanosine triphosphate (GTP). Here, we show that the peptidyl transferase inhibitor sparsomycin triggers accurate translocation in vitro in the absence of EF-G and GTP. Our results provide evidence that translocation is a function inherent to the ribosome and that the energy to drive this process is stored in the tRNA-mRNA-ribosome complex after peptide-bond formation. These findings directly implicate the peptidyl transferase center of the 50S subunit in the mechanism of translocation, a process involving large-scale movement of tRNA and mRNA in the 30S subunit, some 70 angstroms away.

Acylation↗
PubMed1989

Sparsomycin analogs. VI. Synthesis and antitumor activity of octylsparsomycin analogs.

Five sparsomycin analogs (9-13) were prepared and examined for their ability to inhibit deoxyribonucleic acid (DNA) synthesis in L5178Y lymphoma cells. All of the compounds showed significant activity in the DNA synthesis assay. The compounds having Rc configuration exhibited almost the same activities independently of the configuration at the sulfoxide sulfur atom. Among the Sc isomers, the Rs configuration was advantageous for the appearance of activity.

Animals↗
PubMedDate not supplied

Potentiation of cisplatin antitumour activity by Ethyldeshydroxy-Sparsomycin in L1210 leukemia.

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.

Animals↗
PubMedDate not supplied

Modulation of the in vitro cytotoxicity of seven anticancer drugs by protein synthesis inhibition using sparsomycin.

Inhibitors of protein synthesis may modify cell response to cytotoxic drugs. The influence of protein synthesis inhibition using sparsomycin (Sm) on the cytotoxicity of seven classical cytotoxic drugs, 5-FU, ARA-C, MTX, doxorubicin, melphalan, bleomycin and vincristine, was studied. Preincubations, simultaneous incubations and postincubations with Sm were investigated in vitro on CHO cells. Preincubation with Sm antagonized the activity of the S phase specific drugs 5-FU, ARA-C, MTX as well as vincristine, while postincubation with Sm enhanced their effect. A similar pattern was observed with doxorubicin. Preincubation with Sm had a potentiated non-S phase specific like bleomycin and cisplatin, but not melphalan. Postincubation with Sm had a potentiating effect on bleomycin but had no effect on melphalan. These results indicate a strong, schedule dependent effect of Sm on various drugs and suggest some potentially useful combinations to be tested in vivo.

Adjuvants, Pharmaceutic↗
PubMedDate not supplied

Studies on retinotoxic potential of a novel antitumor antibiotic--sparsomycin--in rats.

Sparsomycin (Sm) is a potent inhibitor of protein synthesis with an anticancer potential. Two years after its discovery in 1962 a phase I clinical trial revealed serious drug-induced retinotoxicity. The mechanism of this toxicity still remains unresolved; however, its understanding is important for the reintroduction of Sm or one of its analogues in clinical practice. If Sm penetrates the retina, its toxic effect should be seen as inhibition of a protein(s) vital for the visual function. Treatment of healthy albino rats and Royal College of Surgeon (RCS) rats with subtoxic doses of Sm was unable to produce ocular toxic effects. Disruption of the blood-retina barrier with sodium iodate allowed Sm to decrease opsin content by only 27%. These results strongly indicate that Sm might become retinotoxic solely upon extreme conditions such as permeabilization of the blood-retina barrier which may happen only in some rare pathological situations.

Animals↗
PubMedDate not supplied

Preclinical pharmacokinetics of the antitumor antibiotic deshydroxy-sparsomycin in beagle dogs.

Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.

Animals↗
PubMed1987

In vitro modulation of cisplatin cytotoxicity by sparsomycin inhibition of protein synthesis.

Inhibition of protein synthesis can alter cellular responsiveness to the classical anticancer drugs. The in vitro response of Chinese hamster ovary (CHO) cells to cisplatin with or without sparsomycin (Sm) was studied with the use of [3H]leucine and [methyl-3H]thymidine incorporation and clonogenic assay. Pretreatment of exponentially growing CHO cells with 1 microgram Sm/ml for 3 or 5 hours decreased [3H]leucine incorporation by 20% and resulted in significant resistance to cisplatin (P = .005). Sm in a concentration of 10 micrograms/ml reduced [3H]leucine and [methyl-3H]thymidine incorporation after 3 hours by 92 and 84%, respectively, and resulted in potentiation of the cisplatin cytotoxicity (P = .004). This effect was the same in the case of nonproliferating cells (P = .005), while protection due to Sm (1 microgram/ml) was seen only during cell proliferation. Simultaneous incubation and postincubation with Sm proved to have much less or no potentiating effect on cisplatin. The mechanisms of both protection and potentiation are still not clear, but our data indicate that Sm is a promising drug for further studies on the modulation of the cancer cell response to classical anticancer drugs.

Animals↗