Anticancer regimens containing third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in resistant ovarian carcinoma model

Abstract

Taxanes are widely used in the treatment of ovarian carcinomas. One of the main problems with conventional taxanes is the risk of development of multidrug resistance. New-generation synthetic experimental taxoids (Stony Brook Taxanes; SB-T) have shown promising effects against various resistant tumor models. The aim of our study was to compare the in vitro efficacy, intracellular content, and in vivo antitumor effect of clinically used paclitaxel (PTX) and SB-Ts from the previously tested second (SB-T-1214, SB-T-1216) and the newly synthesized third (SB-T-121402, SB-T-121605, and SB-T-121606) generation in PTX resistant ovarian carcinoma cells NCI/ADR-RES. The efficacy of the new SB-Ts was up to 50-times higher compared to PTX in NCI/ADR-RES cells in vitro. SB-T-121605 and SB-T-121606 induced cell cycle arrest in the G2/M phase much more effectively and their intracellular content was 10–15-times higher, when compared to PTX. Incorporation of SB-T-121605 and SB-T-121606 into therapeutic regimens containing PTX were effective in suppressing tumor growth in vivo in NCI/ADR-RES based mice xenografts at small doses (≤3 mg/kg), where their adverse effects were eliminated. In conclusion, new SB-T-121605 and SB-T-121606 analogs are promising candidates for the next phase of preclinical testing of their combination therapy with conventional taxanes in resistant ovarian carcinomas.

Third-generation taxanes SB-T-121605 and SB-T-121606 are effective in pancreatic ductal adenocarcinoma

“…All tested SB-Ts were more effective than PTX (IC 50 27.62 ± 1.40 nM and 22.41 ± 1.95 nM for Paca-44 and BxPC-3 cell lines, respectively. ( Figure 1 A) However, unlike in our study analyzing PTX-resistant ovarian cancer cells NCI/ADR-RES, 14 where SB-Ts at the highest concentrations after 72 h of incubation caused a reduction in cell viability to 3.6–4.3% of the control, the same incubation time led to the reduction of the Paca-44 cell line viability to 48.1 ± 4.3%, 41.3 ± 6.2%, 33.0 ± 4.3%, and 44.4 ± 1.8% for PTX, SB-T-1216, SB-T-121605, and SB-T-121606, respectively. The viability of BxPC-3 cells was reduced to 27.3 ± 3.7%, 17.1 ± 4.2%, 18.2 ± 1%, and 16.1 ± 2.2% for PTX, SB-T-1216, SB-T-121605, and SB-T-121606, respectively.…”

“…In this pivotal experiment, we demonstrated that the combination of a high dose of conventional PTX with a low dose of the third-generation SB-T is very effective combination regimen. In line with our previous in vitro and in vivo observations of increased systemic toxicity of high doses of third-generation SB-Ts in monotherapy, 14 we used their low dose combination with a high-dose PTX, which is relatively safe. This adjustment allowed us to follow the “three R″ principles in animal research, especially aimed at the reduction of the number of animals and refinement, because the high toxicity of monotherapy of SB-Ts could be avoided.…”

“…The observed results are thus different from our prior investigation on NCI/ADR-RES ovarian cancer cells where second-generation SB-Ts were less effective compared to their third-generation counterparts. 14 It should be the subject of follow-up studies to find out the reasons for this discrepancy and guide the next phase of drug development.…”

“…Recently, they have shown exciting effectiveness in PTX-resistant ovarian carcinoma models both in vitro and in vivo . 14 …”

“…This study aimed to compare the effectiveness of second-generation SB-T (SB-T-1216) and its corresponding derivatives of the third-generation (SB-T-121605 and SB-T-121606) with parent drug PTX in in vitro models of PDAC - pancreatic cell lines Paca-44 and BxPC-3 differing by KRAS mutation status and cell line-derived mouse xenografts (CDX) based on KRAS G12V mutant Paca-44 in vivo . The in vivo efficacy of SB-Ts was assessed in a combination regimen with PTX, as shown by us previously in ovarian cancer models, 14 and compared to PTX alone. This report demonstrates that combined regimens of conventional PTX with third-generation SB-Ts are effective in aggressive pancreatic carcinoma in vivo .…”