Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle

Abstract

The overt effects of the anti-cancer drugs cisplatin (cis-DDP) and taxol appear to be DNA modification and microtubule stabilization respectively, yet the mechanisms by which these drugs elicit tumor cell death are not well understood. In this report cell sensitivities to cis-DDP and taxol were accurately determined as a function of cell proliferation and cell cycle stage. Quiescent fibroblasts restimulated to synchronously enter the cell cycle become maximally sensitive to cis-DDP immediately preceding DNA synthesis, and resistance increases with onset of DNA synthesis. Mid-log proliferating cells were separated into progressive stages of the cell cycle by centrifugal elutriation or by double thymidine (dThd) block. Cells staged by either method are maximally sensitive to cis-DDP in G1, just prior to the onset of DNA synthesis and minimally sensitive in peak DNA synthesis, with entry into S phase resulting in a 2-fold decrease in sensitivity. Cells that remained blocked at the G1/S phase boundary during cis-DDP treatment remain maximally sensitive after release. Sensitivity to taxol increases at 2 points: transiently during transition of normal cells from quiescence to proliferation and steadily as proliferating cells progress from early G1 to late G2. This 3-fold increase in taxol sensitivity through the cell cycle is rapidly reversed upon cell division. Synchronous cells treated with either drug at points of maximum sensitivity initiate apoptotic DNA fragmentation 12-14 hr post-exposure to drug.

Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line

“…We found here that the delay in mitotic exit was associated with apoptosis in the NIH-OVCAR-3 cell line. Several studies have indicated that p34 cdc2 activity mediates apoptotic cell death (Shi et al, 1994;Shimizu et al, 1995), and it has been suggested that p34 cdc2 plays a role in paclitaxel induced-apoptosis (Donaldson et al, 1994). In the present study, we found that a prolonged activation of p34 cdc2 in the absence of p21 expression was associated with apoptosis, whereas apoptosis did not occur when p21 was elevated enabling an earlier inhibition of p34 cdc2 activity.…”

Differential modulation of paclitaxel-mediated apoptosis by p21Waf1 and p27Kip1

“…Previous research has shown the temporal association of paclitaxel-mediated apoptosis and p34cdc2 activation, and also has demonstrated the attenuation of paclitaxel-mediated apoptosis by inhibition of p34cdc2 activity (Donaldson et al, 1994;Shen et al, 1998;Yu et al, 1998). These studies concluded that the activity of p34cdc2 was required for paclitaxelmediated apoptosis (Yu et al, 1998).…”

“…In the induced RKO cells, the cell cycle was arrested wholly in G1 phase by p27 Kip1 and in G1 and G2/M by p21 Waf1 (Figure 2b), whereas the increased p34cdc2 activity and cell cycle arrest associated with paclitaxel treatment is known to occur in G2/M phase (Donaldson et al, 1994). We therefore sought to determine in which phase RKO cells accumulated when they were treated with paclitaxel and were subsequently induced to express p21 Waf1 or p27 Kip1 .…”

In vivo evaluation of the mutagenic potential and phytochemical characterization of oleoresin from Copaifera duckei Dwyer

“…Sena and Chen (1998) used the micronucleated cell assay and Swiss albino mice to evaluated the in vivo bone marrow cell mutagenic potential of 25, 50 and 80% of the LD 50 dose of orally administered Copaifera langsdorfii oleoresin and demonstrated a statistically significant increase micronucleated cells (and hence mutagenic action) 836 Maistro et al only at high doses, although these authors used a higher maximum dose than we did. Donaldson et al (1994) extensively investigated the cytotoxicity of the antimitotic antitumor diterpene taxol derived from the yew tree Taxus brevifolia and showed that the antimitotic effect of taxol classified it as an important anticancer agent. A genotoxicity study by Dias et al (1997) showed that taxol had no radio-sensitizing effect on chromosomal aberrations induced by gamma radiation and also did not increase doxorubicin-induced chromosomal aberrations in in vitro Chinese hamster ovary cells.…”