homoharringtonine and Leukemia-P388

Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.

Topics: Alkaloids; Animals; Cell Survival; Cytarabine; Doxorubicin; Drug Resistance; Female; Gene Amplification; Harringtonines; Homoharringtonine; Leukemia P388; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Tumor Cells, Cultured; Vincristine

Topics: Alkaloids; Animals; Female; Harringtonines; Homoharringtonine; Leukemia P388; Mice; Mice, Inbred DBA; Neoplasms, Experimental; Phenobarbital

Topics: Alkaloids; Animals; Cells, Cultured; Cytoplasm; Harringtonines; Homoharringtonine; Leukemia P388; Leukemia, Experimental; Mice; Mitochondria; Ribosomes

Topics: Alkaloids; Animals; Cell Cycle; Flow Cytometry; Harringtonines; Homoharringtonine; Leukemia P388; Leukemia, Experimental; Mice

The antitumor activities and the mechanisms of action of harringtonine and homoharringtonine, alkaloids isolated from cephalotaxus hainanensis Li, were compared to those of vincristine. The results obtained were as follows: Harringtonine and homoharringtonine Significantly inhibited the growth of L1210 cells in culture. The IC50 values were similar to that of vincristine. Harringtonine and homoharringtonine had little effects on changes in the DNA histograms of FL cells at any concentrations, which suggesting that these drugs prolong the duration of each phase of the cell cycle evenly. Harringtonine and homoharringtonine had only a minor effect in arresting P388 cells in mitosis. Harringtonine significantly inhibited the DNA synthesis of P388 leukemia cells in culture, while vincristine weakly inhibited RNA and DNA synthesis. The successive treatment with harringtonine and homoharringtonine were as effective as the successive treatment with vincristine against P388 and L1210 leukemia, while both drugs were ineffective against Lewis lung carcinoma.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Cell Division; Cell Survival; Cells, Cultured; DNA Replication; Flow Cytometry; Harringtonines; Homoharringtonine; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mice; Vincristine

Antitumor activities of harringtonine(HA) and homoharringtonine(HO) both belong to cephalotaxus alkaloids were compared with those of vinca alkaloids, vincristine (VCR) and vinblastine (VLB). HA and HO had significant activities against P388 leukemia, L1210 leukemia and B16 melanoma by intraperitoneal injection comparable to VCR and VLB. The therapeutic index (LD10/ED50) of HA and HO in B16 melanoma system was 1.90 and 2.31, while those of VCR and VLB were 1.38 and less than 1.00, respectively. The oral administration of these cephalotaxus alkaloids evoked a significant antitumor activity but that of vinca alkaloids induced no activity against P388 and B16 melanoma. The efficacy of HO on various tumor systems was equal or greater than that of HA when comparison was made between these two cephalotaxus alkaloids. In contrast to VCR and VLB, HA and HO demonstrated moderate activity against P388/VCR, a subline of P388 resistant to vincristine. The intraperitoneal injection of VCR or VLB produced an increase in the mitotic index of P388 cells as compared with the control values, but HA or HO decreased it. HA and HO, cephalotaxus alkaloids are a new class of active compounds of plant origin which may differ from the vinca alkaloids in the mechanism of antitumor activity.

Topics: Administration, Oral; Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Injections, Intraperitoneal; Leukemia P388; Male; Melanoma; Mice; Mitotic Index; Neoplasms, Experimental; Vinblastine; Vincristine