Imaging lesions are the first factor that is considered when evaluating OC progression or recurrence. Additionally, the role of cancer antigen CA-125 elevation in the assessment should be carefully assessed. Both the progression-free interval and platinum-free interval define recurrence or progression according to Response Evaluation Criteria in Solid Tumor (RECIST) [9,10]. In 2000, the Gynecologic Cancer Intergroup expanded the definition of recurrence or progression of OC based on changes in the CA125 concentrations [11]. Based on the progression or recurrence of CA125 criteria and considering that maintenance therapy may have an impact on the sensitivity of patients to platinum, experts at the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer Intergroup suggested that CA125 should be part of the platinum sensitivity evaluation criteria in OC. It should be noted that in assessing the date of progression, RECIST should be prioritized [12]. Moreover, the platinum-free interval or progression-free survival evaluated under the two distinct criteria should not be compared together.
Nero 14 platinum serial key
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Radiotherapy is also a form of palliative care for PROC. Historically, whole-abdominal radiotherapy was an option for early-stage and minimally residual advanced-stage ovarian carcinoma. Since the 1980s, platinum-based systemic chemotherapy has gradually replaced whole-abdominal radiotherapy for the management of OC. In recent years, radiotherapy has been used to control symptoms, improve tolerance, and increase the efficacy of chemotherapy, targeted therapy, and immunotherapy in patients with advanced OC, especially those with chemotherapy-resistant OC [24].
Several studies have shown that ATRis can reverse the resistance of cancer cells to platinum. Studies have shown that disruption of ATR function through depletion or kinase-dead protein expression could influence the survival of several cancer cell lines, including osteosarcoma cancer cells, lung cancer cells, and colon cancer cells, with or without DNA-damaging agents. More importantly, the tumor cell killing effect was more pronounced when combined with other chemotherapy agents, the most significant of which were the cross-linking drugs cisplatin and carboplatin [50]. This finding provides a potential strategy for platinum-based compounds in the treatment of PROC. In a study by Hall et al. [51], the addition of VX-970 significantly increased the sensitivity to platinum in vitro in non-small cell lung cancer that was previously insensitive to platinum. Moreover, VX-970 had the most obvious synergistic effect on the cells with the lowest initial platinum response. Platinum and VX-970 also showed a significant synergistic effect in a xenograft model. A study showed depletion of ATR with siRNAs that sensitized OVCAR-8 cells, a kind of OC cell line, to platinum, topotecan, and veliparib exposure. Similar results were obtained when the researchers used VE-821 to inhibit ATR. Moreover, ATRi might sensitize cells by altering the phosphorylation of other currently unclear substrates rather than Chk1 Ser345 [52]. Another study showed that inhibition of the ATR/CHK1 pathway reversed CXCL2-mediated platinum resistance in HGSOC cells [53].
Multiple studies have shown that combination therapy with PARPi and ATRi, especially long-term ATRi, is very promising. In 2013, Huntoon et al. [52] reported that VE-821 significantly enhanced the sensitivity of OC cell lines with BRCA deficiency to veliparib (a kind of PARPi). Thereafter Kim et al. [65] demonstrated the synergistic effect of AZD6738, a kind of ATRi, combined with PARPis in HGSOC both in vivo and in vitro. The use of PARPis increased the ATR/CHK1 pathway dependence in HGSOC with mutated BRCA. The combination of PARPis and ATRis resulted in cell retention in the G2-M phase and increased DNA damage and apoptosis. A similar study in 2020 in platinum-resistant or PARPi-resistant OC cells showed that treatment of cells with PARPis increased CHK1 phosphorylation and stagnated G2/M cycle cell growth, and the addition of ATRis reversed these effects. In addition, the colony formation ability of the cell decreased significantly after ATRi-PARPi treatment compared with PARPi treatment alone. To explore the synergistic mechanism of ATRis and PARPis, the accumulation of DNA DSBs in the S phase and the changes in copy fork and apoptotic markers were evaluated after combination treatment. Overall, the results suggested that ATRi-PARPi may increase DNA DSBs in the S phase by increasing RS, ultimately leading to platinum-resistant or PARPi-resistant OC cell death through apoptosis. In mouse PDX models of platinum-resistant and PARPi-resistant OC with BRCA1 mutation or CCNE1 amplification, ATRi-PARPi combination therapy had considerable efficacy and safety [66]. This result provides more evidence for PROC treated with ATRi-PARPi. Dibitetto et al. [44] showed that long-term pretreatment with ATRis selectively induced hypersensitivity of cancer cells to PARPis because of oncogene-induced high RS without interfering with the reactivity of normal cells to PARPis. In the other study [46], researchers found that using ATRis and PARPis after a low-dose, long-term (five days) pretreatment with ATRis to deplete key HR components made cancer cells particularly sensitive to PARPis. This indicates a more likely way to benefit from combination therapy with ATRis and PARPis as follows: a low dose of ATRi pretreatment followed by long-term combination with a PARPi.
On December 10, 2012, a phase I clinical trial of berzosertib was started. This clinical study demonstrated that berzosertib was well tolerated with topotecan in advanced solid tumors (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5) and achieved satisfactory efficacy in platinum-resistant SCLC (3 of 5 derived a durable clinical benefit) [75]. Multiple Phase I trials showed that the recommended phase II dose (RP2D) of berzosertib was 210 mg/m2 with intermittent use of other drugs [76,77,78]. 2ff7e9595c
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