Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.

Synthesis, Characterization and Anticancer Evaluation of Novel Analogues of Pyrazoles

In the present study, a series of novel substituted pyrazole chalcones and pyrazole oximes (CF 1-15) were synthesized and characterized. Logp values were determined to assess their hydrophobicity. MTT (methyl tetrazolium) assay was performed on A-549 (lung cancer) cell lines. The MTT assay results showed the effect of various substituents on the pyrazole template that could influence their cytotoxic effect. Out of the 15 compounds screened against A-549 cell lines, the compound CF-6 showed appreciable cytotoxicity against the standard doxorubicin.

Molecular Docking, G-QSAR Studies, Synthesis and Anticancer Screening of Some New 2-Phenazinamines as Bcr-Abl Tyrosine Kinase Inhibitors

Background: The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity. This strategy of designing compounds possessing selectivity over specific tyrosine kinase has been achieved through G-QSAR and molecular docking studies. Methods: The objective of this research has been to design newer 2-phenazinamine derivatives as Bcr-Abl tyrosine kinase inhibitors by G-QSAR, molecular docking studies followed by wet lab studies along with evaluation of their anticancer potential. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2 followed by wet lab experiments for synthesizing 2- phenazinamine derivatives. The chemical structures of ligands in 2D were drawn by employing Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimised by using semiempirical method called MOPAC. The protein structure was retrieved from RCSC protein data bank as PDB file. The binding interactions of protein and ligands were done by using PYMOL. The molecular properties of the designed compounds were predicted in silico by using Osiris property explorer. Later, we synthesized novel 13 2-phenazinamine derivatives by treating parent compound with various aldehydes in the presence of dicyclohexylcarbodiimide (DCC) and urea to afford 2-(2-chlorophenyl)-3-(phenazin-2-yl) thiazolidin-4-one and another series of derivatives synthesized with different aldehydes in the presence of p-toluylsulphonic acid, diphydropyridine and benzene sulfonyl chloride to afford benzenesulfonyl-N-(2-chlorobenzyl)-phenazin-2-amine. All the derivatives were tested for invitro anticancer activity on K562 human chronic myelogenous leukemia cell line by employing MTT assay method. Results: The developed G-QSAR models were found to be statistically significant with respect to training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892). The best developed G-QSAR model suggested that the XlogP values of phenazinamine derivatives were found to be highly influential in determining biological activity. The standard drug was found to exhibit binding energy - 6.79 kcal/mol and the derivatives 5b and 6c exhibited binding energy of - 7.46 and - 8.51; respectively. Conclusion: Compounds 5b, 6c were observed to possess good lipophilicity and were found to exhibit better activity than other compounds in the series, although less than standard doxorubicin. The synthesis of these 2-phenazinamine derivatives (5a-m) is reported to be obtained from 2,4- dinitrodiphenylamine by applying appropriate synthetic route. Compounds 5b and 6c showed better cytotoxic activity against K562 cancer cell line when compared to other compounds of the series, although less than standard doxorubicin.

Cytotoxic 24-nor-ursane-type triterpenoids from the twigs of Mostuea hirsuta

Two new 24-nor-ursane-type triterpenoids, 2α,3β,19α-trihydroxy-24-norurs-4(23),12-dien-28-oic acid (1) and 3β-acetoxy-2α,19α-dihydroxy-24-norurs-4(23),12-dien-28-oic acid (2), along with 15 known compounds were isolated from the methanol extract of the twigs of Mostuea hirsuta. While 2-hydroxymethylbenzamide (13) was isolated for the first time from the natural source, compounds 3–12 are reported here for the first time from the genus Mostuea. Their structures were elucidated by means of spectroscopic analyses including 1D- and 2D-NMR spectroscopy, high-resolution mass spectrometric data as well as comparison with data from the literature. Compounds 1, 2, 4–9 and 13 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with minimum inhibitory concentrations (MICs) > 1 mg mL–1. However, the respective compounds 1, 2, 8, 9 and 13 exhibited moderate cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 10.6–16.5 μm compared to the standard doxorubicin with IC50 0.9 μm.

Cytotoxic Compounds from Endemic Arnebia purpurea

Phytochemical studies of the roots and aerial parts of endemic Arnebia purpurea S. Erik & H. Sumbul resulted in the isolation and characterization of four naphthoquinones [isovalerylalkannin (1), α-methyl- n-butanoyl alkannin (2), acetylalkannin (3), and alkannin (4)], a triterpene derivative [3- O-acetyl-oleanolic acid (5)], a steroid [β-sitosterol (6)], three flavonoid glycosides [isorhamnetin-3- O-rutinoside (7), kaempferol-3- O-rutinoside (8), kaempferol 3- O-(5″-acetyl) apiofuranoside 7- O-rhamnopyranoside (9)] and a phenolic acid [rosmarinic acid (10)]. 3- O-Acetyl-oleanolic acid, isorhamnetin-3- O-rutinoside, kaempferol-3- O-rutinoside, and kaempferol 3- O-(5″-acetyl) apiofuranoside 7- O-rhamnopyranoside are reported from an Arnebia species for the first time. Cytotoxic activities on L929 murine fibrosarcoma cell line of the isolated compounds were investigated using MTT assay. Naphthoquinones (1–4) showed intermediate cytotoxic activity in comparison with the standard, doxorubicin.

A Chronopharmacological Study Related to Doxorubicin Based Bone Marrow Suppression

Myelosuppression is the most common toxicity of anti-neoplastic therapy due to inhibition of cell replication in bone marrow. This can be minimized by administering drugs on the basis of circadian time basis. Hence the aim is to study circadian time cycle related bone marrow suppression variation resulting from doxorubicin based cancer chemo therapy regimen. A prospective observational clinical study based on circadian time Cycle was done for a period of six months at a tertiary care hospital. Standard doxorubicin Regimen was given in the dose of 60 mg/m as iv infusion. Each cycle is repeated every 21 Days. Complete hemogram was done on day 0 and day 10 of both day and night cycle. Results were analyzed using students paired t test. It was found that during Night cycle therapy bone marrow suppression was minimal and statistically significant (p<0.001). Chronotherapy is useful in minimizing bone marrow toxicity.DOI: http://dx.doi.org/10.3329/ijpls.v2i5.17627 International Journal of Pharmaceutical and Life Sciences, Volume 2(5) Dec 2013: 197-201

Phase Ib/II study of INNO-206 (EMCH-doxorubicin) in patients with soft tissue sarcoma.

10036 Background: The safety and preliminary tumor response of a doxorubicin conjugate, INNO-206, was evaluated primarily in patients with metastatic STS who progressed on prior chemotherpy. INNO-206 consists of doxorubicin attached to an acid-sensitive linker that binds covalently to cysteine-34 in circulating albumin. Methods: INNO-206 was administered IV at doses of either 230, 350 and 450 mg/m2 (165, 260 and 325 mg/m2 dox. eq.) every 21 days for up to 8 consecutive cycles. Subsequent dose levels were administered if < 2/5 or 4/8 patients experienced a non-hematological dose-limiting toxicity during Cycle 1. Tumor response was monitored every other month and treatment continued until tumor progression or unacceptable toxicity. Standard safety monitoring was performed and cardiac function was followed periodically using MUGA or cardiac ultrasound. Results: As of January 11, 2012, 25 patients were entered in the study. 21/25 patients had STS of various types. Of the 5 patients treated at 230 mg/m2 INNO-206, 1 subject had grade 3 fatigue and acid reflux. Of the initial 5 patients entered at the 350 mg/m2 dose, no individuals experienced a grade 3 or 4 non-hematological toxicity during cycle 1. 2 patients treated at the 450 mg/m2 dose developed grade 3 oral mucositis during cycle 1. No patient exhibited cardiotoxicity as determined by MUGA or cardiac ultrasound. The MTD was determined to be 350 mg/m2 INNO-206 (260 mg/m2 dox.eq.). 15 more patients were entered at this dose (total of 20 patients). Of the 16 patients with STS, 3 objective partial responses (one of whom received prior doxorubicin) are ongoing as well as 10 patients with stable disease (range 2-7 months). 1 patient had progressive disease at the first evaluation. 2 patients died within the first cycle, one due to progressive disease and the other due to sepsis. Conclusions: INNO-206 is an active drug for the treatment of patients with advanced STS who have failed prior chemotherapy. Cumulative doses of 2000 mg/m2 of doxorubicin equivalents have been achieved, which is over 3 1/2 x the peak cumulative dose of standard doxorubicin. Adverse events are primarily hematological and no cardiotoxicity has been observed.

Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma

In the present study, we evaluated the efficacy and safety of rituximab in combination with standard doxorubicin, bleomycin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lymphoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m2 weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respectively. The 5-year EFS for patients with stage III/IV cHLwas 82%. Furthermore, the 5-year EFS for patients with an International Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in patients with advanced-stage cHL. These data are currently being confirmed in a multicenter randomized trial. This trial has been completed and is registered with www.clinicaltrials.gov as NCT00504504.

Non-Pegylated Lyposomal Doxorubicin, Cyclophosphamide, Vincristine, Prednisone and Rituximab (R-COMP) as Initial Treatment for Patients with Splenic Marginal Zone Lymphoma (SMZL). A GISL Study

Background: SMZL is an indolent lymphoma, presenting with massive splenomegaly generally associated with intrasinusoidal bone marrow infiltration. The encapsulation of doxorubicin into non-pegylated liposomes allows targeting of the drug to affected organs including spleen, lymphnodes and bone marrow. Methods: In 2005 the GISL started a phase II study for the treatment of patients with histologically confirmed SMZL, investigating safety and clinical profile of 6 courses of a modified R-CHOP regimen in which standard doxorubicin was substituted with non pegylated lyposomal doxorubicin (NPLD) used at the same doses (50mg/m2) (R-COMP). Main inclusion criteria were age > 18 yrs, normal cardiac function and active disease (at least one of the following; Hb <10g/dl; plt <100.000/mmc, symptomatic splenomegaly, elevated LDH, B symptoms, extrasplenic disease, LDT <12 months). Splenectomy was allowed prior to treatment start only in case of symptomatic spleen enlargement. The study was planned according to a two-stage Simon design using overall response rate as primary endpoint. We present the results of the analysis performed after the completion of study stage 1. The access to stage 2 is allowed if at least 12 responses are recorded among among the first 19 evaluable cases. Results: As of January 2007, 20 patient were enrolled with the following characteristics; median age 63 years (30–80), Hb <10g/dl in 20%, Lymphocytes > 5000/mmc in 65%, elevated LDH in 65%; 2 patients were splenectomized before treatment start. One patient was not available for response assessment. A clinical response was observed in all remaining 19 cases (ORR 100%); 12 (63%) cases obtained a CR. So far only one patient progressed at +1 month from treatment. Treatment was well tolerated with grade III/IV neutropenia in 8 patients (42%), grade III pulmonary toxicity in 1 patient and grade II peripheral neuropathy in 5 cases. In one case a reversible cardiac failure was reported after 1 month from the end of treatment. Conclusions: In conclusion 6 cycles of R-COMP combination represent a safe and promising treatment option for patients with clinically active SMZL.