Anti Cancer Drugs

A series of amic acid derivatives of mefenamic acid were synthesized with the aim of inhibitting topical gastrointestinal toxicity of mefenamic acid. The key intermediate amic acid (III) was prepared from the reaction of acid hydrazid of mefenamic acid(II) with phthalic anhydrides in dry actone. The new type of imide compound (IV) was dehydrated the amic acid(III) with acetic anhydrous and sodium acetate. The esterification of hydroxyl groups of amic acid (III) produce corresponding ester(V), which was condensed with hydrazine hydrate to give acid hydrazide (VI), then the later compound reacted with syringaldehyde in dry benzene to yield new schiff base (VII). The new derivatives containing heterocyclic unit (VIII)-(X), four and five, member ring were successfully formed such as azetidin-2-one, thiazolidin-4-one, and,imidazolidin-4-one. The structures of the synthesized compounds were confirmed using FTIR, 1HNMR, Mass and CHN-S. The antibacterial activities of some synthesized compounds were screened and showed a highest or low inhibition against Staph.aureus (G+), Bacillus subtilisa (G+), Klebsiella pneumoniae (G-), and E.coli (G-). Also, The cytotoxic effect of different concentrations of some the synthesized compounds was tested against MCF-7 cell line (human breast carcinoma cells) and positive results were obtained for some of them, which encouraged us to study the toxicity using living organisms (mice) to evaluate its acute toxicity and proved the resules of non-toxicity of the derivatives.

The clinical efficacy and antiangiogenic effect of low-dose, metronomic administration of cyclophosphamide (CTX) and methotrexate (MTX) (CM) have been demonstrated. The authors report results and long-term follow-up for patients with metastatic breast carcinoma who obtained prolonged clinical benefit with CM. Prospectively collected data from two successive clinical trials were evaluated. From July 1997 to October 2003, patients with metastatic breast carcinoma were treated with low-dose oral chemotherapy (MTX 2.5 mg, twice daily on day 1 and day 2 or 4, and CTX 50 mg daily). Patients who achieved prolonged clinical benefit for a duration of 12 months or more (complete remission, partial remission or stabilization of disease) were considered for the analysis. Median follow-up was 23 months. A total of 153 patients were enrolled and are evaluable: Eastern Cooperative Oncology Group performance status 0-1 in 90 patients, two or more sites of metastatic disease in 97 patients, zero reg...

A flow tube reactor containing iron or zinc powder in a nitrogen atmosphere is capable of performing >90% anaerobic reductive dehalogenation of the cancer drugs ifosfamide and cyclophosphamide at 400 °C using toluene, alcohol or water as proton donors and iron or zinc as reducing agents. The products are all chlorine-free, as proven by GC-MS. The process is particularly interesting for large-scale industrial applications.

The purpose of this study was to explore the feasibility and toxicity of intrapatient dose adjustment using predefined levels of exposure to cisplatin, with the ultimate goal to further improve the antitumor activity of the treatment. The primary parameter for adaptive dosing was the level of platinum DNA adducts in peripheral white blood cells (WBC) and the secondary parameter the area under the curve (AUC) of unbound platinum in plasma, which were determined during the applied courses. Target levels had been defined in a previously performed pharmacologic study. The concept of adaptive dosing was tested in 16 patients with locally advanced head and neck (H/N) cancer who would receive six weekly courses of cisplatin at a starting dose level of 80 mg/m(2), which was previously investigated in a phase II study. Forty-seven percent of patients received a dose increase varying from 10 to 40%. Only two patients had exposure levels significantly below the defined target levels for DNA adducts and AUC. The majority of patients reached the defined target levels by modest dose increases of 10-20% during course 2. Relevant but reversible ototoxicity (temporary grade 3 in two patients) and renal toxicity (temporary grade 2 in two other patients) were observed. The pattern and severity of the toxicity was comparable to that encountered in the previous phase II study in H/N cancer patients. We conclude that the strategy of intrapatient dose adjustment for cisplatin is practically feasible in a research setting even when a short turn around time of 1 week is the limit for reporting results. Although in some patients the dose increase that had to be applied to reach target levels was substantial (up to 40%), this approach in H/N cancer patients is not expected to improve the response rate significantly, because these significantly underdosed patients represented only a small percentage of the investigated population. The great majority of patients needed only limited (10-20%) dose increases which very likely will not improve the response rate to a clinically significant extent. The outlined concept is currently being explored in other tumor types and schedules of cisplatin.

The purpose of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) versus conventional non-PBC regimens in a metastatic triple-negative breast cancer (TNBC) setting. We reviewed the electronic patient records of patients with confirmed metastatic TNBC at four major cancer centres in Canada. All patients were allocated into two groups based on type of chemotherapy received (PBC vs. non-PBC) and line of treatment (first-, second-, or third-line). The primary objective of this study was to evaluate the efficacy of PBC in metastatic TNBC in terms of median duration of overall survival (OS) from diagnosis of distant metastatic disease and compare it with the efficacy of conventional non-platinum-based chemotherapy in metastatic TNBC after controlling for known prognostic factors. A total of 153 metastatic TNBC patients were identified, 58 treated with PBC and 95 with non-PBC. The median time in first-line PBC versus non-PBC was not different between the two group...

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in th...

We conducted a phase II study to determine the availability and safety of combination chemotherapy with weekly paclitaxel and doxifluridine (a capecitabine metabolite) in the treatment of advanced or recurrent breast cancer. Patients were treated with a combination chemotherapy regimen: doxifluridine was orally administered at 800 mg/day for 14 days, followed by a 7-day washout period. Paclitaxel was given intravenously on days 1 and 8 at 80 mg/m2 for 1 h, followed by a 1-week washout period. This 3-week cycle of therapy was repeated as long as possible (at least eight cycles) until the progression of the tumor and drug-related adverse effects were no longer observed. From May 2003 to December 2005, 26 patients were enrolled in the study. The overall response rate was 53.8% (95% confidence interval, 33.4-73.4%). The clinical benefit rate, including long-term no change, was 65.4% (95% confidence interval, 44.3-82.8%). Time to progression and survival time were 297 and 1182 days, respectively, for the 26 enrolled patients. No severe toxicities were observed. Grade 3/4 leucopenia in three patients, neutropenia in five patients, increased serum creatinine in three patients, hypercalemia in one patient, hypocalcemia in one patient, nausea/vomiting in two patients, and diarrhea in one patient. The good response rate and long time to progression and overall survival time of this doxifluridine combined with weekly paclitaxel therapy indicate its potential as a first-line or second-line treatment for advanced or recurrent breast cancer patients.

Breast cancer is the most common female tumour type and accounts for the leading cancer mortality in women worldwide. Up to 75% of breast cancers express the oestrogen receptor or progesterone receptor (hormone-receptor–positive). Aromatase inhibitors were the preferred first-line treatment option. New and acquired resistance to hormonal blockade has led to the development of targeted treatments. Cyclin-dependent kinases (CDKs) are a large family of serine–threonine kinases that play an important role in regulating cell cycle progression: palbociclib, ribociclib, and abemaciclib. We conducted a study to evaluate the efficacy of CDK inhibitors (CDKi) plus aromatase inhibitor in hormone-receptor–positive/HER2-negative ABC patients with visceral disease, postponing the use of chemotherapeutic agents and strengthening the power of endocrine agents. We enrolled 22 patients treated with CDKi (palbocilib) plus aromatase inhibitor (group A) and 38 patients treated with chemotherapy (group B...

Cisplatin is one of the most active and widely used anticancer drugs; however, its clinical efficiacy is often limited by the development of resistance. Since several studies indicated that ras oncogenes may modulate the cellular response to cisplatin or radiation, we investigated the gene-specific repair of the N-ras gene in the human K 562 cell line after exposure to cisplatin using a novel nonradioactive polymerase chain reaction inhibition assay. This assay is based on the fact that DNA lesions can block the Taq polymerase and thereby result in a decreased amplification of a damaged segment compared to the amplification of the same segment in a non-damaged template. The overall genomic repair rate was measured by atomic absorption spectroscopy. Immediately after cisplatin exposure no amplification segment was observed. However, a complete restoration of the N-ras gene (2.4 kb) was seen after 8 h posttreatment incubation. In contrast, only 60% of the overall genome was repaired at this time. Our results clearly indicate that cisplatin-induced DNA lesions are more efficiently removed from transcribed regions within the DNA, suggesting that the efficiency of DNA repair in a given gene may be correlated to its transcriptional activity. Since ras oncogenes control several cellular signal transduction pathways, known to be involved in DNA damage response, preferential repair of the N-ras gene could therefore be an important step to prevent inactivation of cellular defense mechanisms after exposure to genotoxic agents.