Correlation of the in vitro cytotoxicity of ethyldeshydroxysparsomycin and cisplatin with the in vivo antitumour activity in murine L1210 leukaemia and two resistant L1210 sublcones

Abstract

The cultured murine leukaemia L1210 cell populations used in the present study were derived from L1210 cells that had been grown in vivo. Subclones resistant to sparsomycin (L1210/Sm) or cisplatin (L1210/CDDP) were also developed in vivo. The doubling times of the cultured cell populations were identical. Fractions surviving after drug treatment in vitro were determined by colony formation in soft agar. The results, based on the differential sensitivity of the cell populations to ethyldeshydroxysparsomycin (EdSm) and CDDP, indicated that after a short exposure, cultured L1210/CDDP cells were cross-resistant to EdSm. L1210/Sm cells, however, were not cross-resistant to CDDP. The results obtained in cultured cell populations were confirmed in vivo. CD2f1 mice bearing i.p. implants of 1 x 10(5) tumour cells were given EdSm or CDDP and a combination of the two agents. Drugs were given once daily every 4 days for 3 doses starting at 24 h after tumour implantation. Treatment of mice bearing L1210/wt leukaemia with combined EdSm and CDDP caused strongly synergistic antitumour activity. In animals bearing the two resistant subclones, however, combined drug treatment did not improve the antitumour activity. The corresponding median survival of mice receiving combined drug treatment was 60 days in each group containing 6 mice bearing L1210/wt, with 4-6 cures being noted; 19 days in animals harbouring L1210/Sm, with 2 cures being recorded among 6 mice; and 11 days in mice bearing L1210/CDDP, with no cure being obtained. The results of this study indicate that the synergism resulting from combined treatment with CDDP and EdSm is a function of the cellular properties of the target tumour-cell populations and is independent of host factors.

Sparsomycin – a Review and Re-assessment

“…An extended study with 60 (5 mg/kg) with cisdiamminedichloroplatinum(II) (CDDP) (3 mg/kg) produced 80% cures in mice treated with L1210 leukemia cells. 63,64 Further research established that 60 decreased the cellular protein levels and the overall glutathione S transferase activity in opposition to cisplatin which has detoxifying effects. 65 As a single agent, when administered i.p.…”

Hybrids of antibiotics inhibiting protein synthesis. Synthesis and biological activity

“…The design of sparsophenicol (lb) was based on a hypothesis10•14 stipulating that antibiotics inhibiting protein synthesis and carrying an acylamido function attached to a D-aminopropanol moiety (structure 8), such as chloramphenicol (la), sparsomycin (2b), and lincomycin (5c), can be regarded as retro-inverso analogues of L-amino acid residue of puromycin (6d, see structure 9) or the terminal 3'-0-(aminoacyl)adenosme unit of aminoacyl-tRNA. The scope and limitations of this hypothesis can be studied by interchange of acyl residues of la, 2b, and 5c and inhibition of protein synthesis by the resultant hybrids.…”