Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic

2005 ◽  
Vol 15 (Suppl 1) ◽  
pp. 12-17 ◽  
Author(s):  
M. A. Bookman
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Intracellular Transport ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance ◽  
Synthetic Analog ◽  
Nucleoside Transporter ◽  
Collateral Sensitivity ◽  
Resistant Disease ◽  
Interstrand Cross Links

Gemcitabine (2′2′-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2′ position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800–1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14–22% and a median duration of response of 4.0–10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.

scholarly journals Novel epigenetic-metabolic inhibitor combination treatment blocks platinum-induced ovarian cancer stem cell enrichment

2021 ◽  
Author(s):  
Riddhi Sood ◽  
Sikai Xiao ◽  
Shruthi Sriramkumar ◽  
Christiane Hassel ◽  
Kenneth P. Nephew ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Dna Methyltransferases ◽  
Metabolic Inhibitor ◽  
Platinum Resistance ◽  
Dna Hypermethylation ◽  
Ovarian Cancer Stem Cells ◽  
Promoter Dna ◽  
Rate Limiting ◽  
Platinum Agents

AbstractHigh grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent ovarian cancer is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels throughBRCA1promoter DNA hypermethylation. In a parallel pathway associated with G2/M arrest, platinum treatment also induced an increase in expression ofNAMPT, the rate limiting regulator of NAD+production from the salvage pathway, and NAD+levels, the cofactor required for ALDH activity. Both decreased BRCA1 and increased NAD+levels were required for the platinum-induced enrichment of OCSCs, and inhibition of both DNA methyltransferases (DNMT) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. We conclude that these two separate pathways lead to platinum-induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC reoccurrence.

scholarly journals Trabectedin for reversing platinum resistance and resensitization to platinum in patients with recurrent ovarian cancer

2019 ◽  
Vol 15 (3) ◽  
pp. 271-280 ◽  
Author(s):  
Antonio Casado ◽  
Hector R Callata ◽  
Aranzazu Manzano ◽  
Gloria Marquina ◽  
Teresa Alonso ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance

scholarly journals How to sequence treatment in relapsed ovarian cancer

2020 ◽  
Author(s):  
Sandro Pignata ◽  
Sabrina Chiara Cecere
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Disease ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance ◽  
Front Line ◽  
Related Factors ◽  
Drug Classes ◽  
Stage Disease ◽  
Platinum Based Chemotherapy ◽  
Line Setting

Numerous disease- and patient-related factors must be considered when selecting systemic therapy for recurrent ovarian cancer. Anti-angiogenics (bevacizumab) and poly(ADP-ribose) polymerase inhibitors (olaparib, niraparib, rucaparib) have an important role as maintenance of platinum-based chemotherapy for recurrent disease and their use in the first-line setting of advanced-stage disease is becoming established. As previous exposure to none, one or both of these drug classes is integral to selecting next therapy, front-line use impacts on options available to treat recurrent disease. A key strategy to delay platinum resistance and improve prognosis of recurrent disease is to alternate treatments with different mechanisms of action. The multiple mechanisms of trabectedin and its complementarity with platinum allow intercalation between platinum regimens in potentially platinum-responsive patients with recurrent disease.

Expression of multidrug resistance marker MDR1 in patients with ovarian cancer and its possible predictive significance.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17530-e17530
Author(s):  
Elena P. Ulianova ◽  
Darya Yu. Yakubova ◽  
Aleksandr B. Sagakyants ◽  
Galina V. Zhukova ◽  
Evgeniya M. Nepomnyashchaya ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Tumor Cells ◽  
Detection System ◽  
Chemotherapeutic Agents ◽  
Platinum Resistance ◽  
Mdr1 Expression ◽  
Analysis Of Results ◽  
Group 2 ◽  
Group 1

e17530 Background: Despite the progress made in diagnosis and treatment, ovarian cancer (OC) is still the third most common genital cancer. Poor results of therapy for various forms of OC stimulate the search for fundamentally new approaches to the treatment. One of the main reasons for resistance to chemotherapeutic agents includes multidrug resistance (MDR) of tumor cells. The most characterized of its various mechanisms is the elevated activity of the ABC family protein - ABCB1 (Pgp or MDR1). The purpose of the study was evaluation of the expression of this ABC transporter as a predictive factor in platinum-containing chemotherapy in OC patients. Methods: 100 patients aged 29-79 years with advanced stage IIIC - IV OC with/without ascites were recruited between 2016 and 2020. Depending on the treatment results, patients were divided into 2 groups: group 1 (n = 59) - patients with platinum sensitivity; group 2 (n = 41) - patients with platinum resistance during the treatment or within 6 months after its completion. IHC analysis was performed using rabbit polyclonal anti-MDR1 antibodies (Affinity Biosciences) diluted 1:600 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. MDR1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: Patients with MDR1+ prevailed in group 2 (98%), and patients with MDR1- in group 1 (32%). The average expression of MDR1 in tumor cells in group 2 (64.0±7.0) was statistically significantly higher by 1.7 times (p = 0.003) than in group 1 (37.2±6.8) by the Mann-Whitney U-test. When distributed according to Pearson's χ2 criterion, positive MDR1 as a risk factor in the platinum-resistant group increased the risks of refractory to platinum therapy by 19 times (95% CI 2.4-148.8). Conclusions: The study demonstrated predictive significance of the MDR1 biomarker in platinum treatment in patients with ovarian cancer.

A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5558-5558
Author(s):  
C. N. Landen ◽  
R. Coleman ◽  
M. R. Milam ◽  
T. Johnston ◽  
R. Iyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Stable Disease ◽  
Performance Status ◽  
Single Agent ◽  
Optimal Dose ◽  
Recurrent Ovarian Cancer ◽  
Cytotoxic Agents ◽  
Pharmacokinetic Data ◽  
Resistant Disease

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

Oxaliplatin salvage for recurrent ovarian cancer: A single institution's experience in patient populations with platinum resistant disease or a history of platinum hypersensitivity

2014 ◽  
Vol 134 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Sarah E. Taylor ◽  
Tiffany L. Beck ◽  
Thomas C. Krivak ◽  
Kristin K. Zorn ◽  
Joseph L. Kelley ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
History Of

scholarly journals Metronomic oral cyclophosphamide in relapsed ovarian cancer

2021 ◽  
pp. ijgc-2021-002467
Author(s):  
Pavlina Spiliopoulou ◽  
Samantha Hinsley ◽  
Iain A McNeish ◽  
Patricia Roxburgh ◽  
Ros Glasspool
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Clinical Activity ◽  
Platinum Resistance ◽  
Free Survival ◽  
Disease Response ◽  
Metronomic Cyclophosphamide

ObjectivesTo describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response.MethodsWe retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated.Results50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status).ConclusionOral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.

scholarly journals Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: A case report and review of the literature

2010 ◽  
Vol 18 (1-2) ◽  
pp. 32-35 ◽  
Author(s):  
Rajul Kothari ◽  
Peter Argenta ◽  
Jeffrey Fowler ◽  
Jori Carter ◽  
William Shimp
Keyword(s):  
Ovarian Cancer ◽  
Hormonal Therapy ◽  
Recurrent Ovarian Cancer ◽  
Review Of The Literature ◽  
Stage Iiic ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
Previously Treated ◽  
Low Toxicity ◽  
Antiestrogen Therapy

Hormonal therapy for adjuvant treatment of ovarian cancer may provide a low toxicity option in some patients with refractory disease. A 53 year-old patient with stage IIIC papillary serous ovarian cancer previously treated with multiple chemotherapy regimens with platinum-resistant disease was treated with antiestrogen therapy for 28 months before requiring reinstitution of cytotoxic chemotherapy. Hormonal therapy may be effective in a subset of epithelial ovarian cancer patients with endocrine sensitivity and should be considered in the treatment of platinum-resistant patients.

Sign in / Sign up

Export Citation Format

Share Document