Randomized Controlled Trial

Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study.

Authors: H Hagberg, C Gisselbrecht, ...

The multicentre phase III CORAL study aims to guide choice of salvage chemotherapy in diffuse large B-cell lymphoma (DLBCL) and assess the role of rituximab maintenance after autologous stem cell transplantation (ASCT). Patients are first randomised between ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, ara-C and cisplatin), both combined with rituximab (R-ICE or R-DHAP). After three courses, responders are treated by ASCT with BEAM. A second randomisation then allocates patients to maintenance treatment with rituximab 375 mg/m(2), one injection every 2 months six times, or observation. Accrual to the study is now proceeding well and the planned 400 patients are likely to be enrolled within the next 1.5 years. Results to date are very preliminary but suggest encouraging rates of response. However, they also indicate that initial exposure to rituximab may increase the difficulty of salvaging patients who fail first-line therapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carmustine; Cisplatin; Combined Modality Therapy; Cytarabine; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Hodgkin Disease; Humans; Ifosfamide; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Podophyllotoxin; Remission Induction; Rituximab; Salvage Therapy; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous; Treatment Outcome

PubMed: 16702182
DOI: 10.1093/annonc/mdj996

Review

Authors: Charles M Kodner, Soraya Nasraty

Genital warts caused by human papillomavirus infection are encountered commonly in primary care. Evidence guiding treatment selection is limited, but treatment guidelines recently have changed. Biopsy, viral typing, acetowhite staining, and other diagnostic measures are not routinely required. The goal of treatment is clearance of visible warts; some evidence exists that treatment reduces infectivity, but there is no evidence that treatment reduces the incidence of cervical and genital cancer. The choice of therapy is based on the number, size, site, and morphology of lesions, as well as patient preferences, cost, convenience, adverse effects, and clinician experience. Patient-applied therapy such as imiquimod cream or podofilox is increasingly recommended. Podofilox, imiquimod, surgical excision, and cryotherapy are the most convenient and effective options. Fluorouracil and interferon are no longer recommended for routine use. The cost per successful treatment course is approximately dollars 200 to dollars 300 for podofilox, cryotherapy, electrodesiccation, surgical excision, laser treatment, and the loop electrosurgical excision procedure.

Topics: Algorithms; Aminoquinolines; Condylomata Acuminata; Cryotherapy; Decision Trees; Diagnosis, Differential; Electrosurgery; Evidence-Based Medicine; Family Practice; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Imiquimod; Keratolytic Agents; Laser Therapy; Male; Patient Selection; Podophyllotoxin; Practice Guidelines as Topic; Primary Health Care; Treatment Outcome

PubMed: 15617297
DOI: No ID Found

Authors: Igor V Magedov, Nikolai M Evdokimov, Menuka Karki...

A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Crystallography, X-Ray; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Jurkat Cells; MCF-7 Cells; Models, Molecular; Molecular Structure; Podophyllotoxin

PubMed: 22986348
DOI: 10.1039/c2cc35044k

Authors: Tobias Cohen, Toni M Schwarz, Frederic Vigant...

Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.

Topics: Antiviral Agents; Cell Line; Cytomegalovirus; Herpesvirus 1, Human; Humans; Podophyllotoxin; RNA Viruses; Tubulin Modulators; Virus Internalization

PubMed: 27783035
DOI: 10.3390/v8100295

Review

Authors: Lu Jin, Zhijun Song, Fang Cai...

Plants containing podophyllotoxin and its analogues have been used as folk medicines for centuries. The characteristic chemical structures and strong biological activities of this class of compounds attracted attention worldwide. Currently, more than ninety natural podophyllotoxins were isolated, and structure modifications of these molecules were performed to afford a variety of derivatives, which offered optimized anti-tumor activity. This review summarized up to date reports on natural occurring podophyllotoxins and their sources, structural modification and biological activities. Special attention was paid to both structural modification and optimized antitumor activity. It was noteworthy that etoposide, a derivative of podophyllotoxin, could prevent cytokine storm caused by the recent SARS-CoV-2 viral infection.

Topics: Humans; Podophyllotoxin; Antineoplastic Agents, Phytogenic; Structure-Activity Relationship; COVID-19; SARS-CoV-2

PubMed: 36615496
DOI: 10.3390/molecules28010302

Authors:

Topics: Brain Neoplasms; Etoposide; Female; Humans; Podophyllotoxin; Pregnancy; Trophoblastic Neoplasms; Uterine Neoplasms

PubMed: 2991763
DOI: 10.1056/NEJM198508223130815

Review

Authors: Qinghua Cui, Ruikun Du, Miaomiao Liu...

Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.

Topics: Antiviral Agents; Benzodioxoles; Biological Products; Biphenyl Compounds; Drug Development; Furans; Lignans; Masoprocol; Plants; Podophyllotoxin

PubMed: 31906391
DOI: 10.3390/molecules25010183

Review

Authors: Zinnia Shah, Umar Farooq Gohar, Iffat Jamshed...

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cytokine Release Syndrome; Drug Discovery; Drug Repositioning; Humans; Neoplasms; Podophyllotoxin; Podophyllum; COVID-19 Drug Treatment

PubMed: 33921719
DOI: 10.3390/biom11040603

Authors: Yilin Qiao, Nathan K Sunada, Alyssa E Hatada...

Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC against the NB cell lines. These results may lead to safer and more effective treatment options for NB patients especially for those with high-risk NB.

Topics: Antineoplastic Agents; Carboxylic Acids; Cell Line, Tumor; Cell Survival; Child, Preschool; Diterpenes; Drugs, Chinese Herbal; Furans; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Inhibitory Concentration 50; Juniperus; Lignans; Molecular Structure; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phytotherapy; Plant Extracts; Podophyllotoxin; Tetrahydronaphthalenes

PubMed: 31255282
DOI: 10.1016/j.bbrc.2019.06.123

Authors: Jasmine Zain, Ni-Chun Tsai, Joycelynne Palmer...

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemotherapy-sensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCLs. In this phase 1 clinical trial, we tested the addition of β-emitting 90yttrium (90Y)-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, and melphalan) as conditioning for AHCT for patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5, and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure (median time of death, 17 months [range, 9-21]) after AHCT. Median follow-up was 24 months (range, 9-26) overall and 24 months (range, 13-26) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% confidence interval [CI], 34-77) and 68% (95% CI, 42-84), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.ClinicalTrials.gov as #NCT02342782.

Topics: Humans; Hematopoietic Stem Cell Transplantation; Carmustine; Lymphoma, T-Cell, Peripheral; Middle Aged; Female; Male; Melphalan; Adult; Transplantation Conditioning; Antineoplastic Combined Chemotherapy Protocols; Aged; Cytarabine; Transplantation, Autologous; Etoposide; Interleukin-2 Receptor alpha Subunit; Podophyllotoxin; Treatment Outcome

PubMed: 38838232
DOI: 10.1182/bloodadvances.2023012497