Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer

Beldner, Matthew A.; Sherman, Carol A.; Green, Mark R.; Garrett‐Mayer, Elizabeth; Chaudhary, Uma; Kraft, Andrew S.; Montero, Alberto J.

doi:10.1186/1471-2407-7-231

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…This enzyme shows a diffuse pattern of distribution in the nucleoplasm with accumulation in the nucleolus [ 55 ]. The catalytic activity of TOPO I is specifically inhibited by camptothecin, an alkaloid of Camptotheca acuminata and similar drugs, such as topotecan (Hycantina®, GlaxoSmithKline) [ 56 , 57 ] and irinotecan (Camptosar, Pfizer) [ 58 , 59 ]. Camptothecin has powerful anti-tumor activity by inhibiting synthesis of nucleic acids and inducing breaks in DNA molecules ([ 60 ]).…”

Section: Discussionmentioning

confidence: 99%

The effect of 3β, 6β, 16β-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells

Lacouth-Silva¹,

Xavier²,

Setúbal³

et al. 2015

BMC Complement Altern Med

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BackgroundThe Combretum leprosum Mart. plant, popularly known as mofumbo, is used in folk medicine for inflammation, pain and treatment of wounds. From this species, it is possible to isolate three triterpenes: (3β, 6β, 16β-trihydroxylup-20(29)-ene) called lupane, arjunolic acid and molic acid. In this study, through preclinical tests, the effect of lupane was evaluated on the cytotoxicity and on the ability to activate cellular function by the production of TNF-α, an inflammatory cytokine, and IL-10, an immuno regulatory cytokine was assessed. The effect of lupane on the enzymes topoisomerase I and II was also evaluated.MethodsFor this reason, peripheral blood mononuclear cells (PBMCs) were obtained and cytotoxicity was assessed by the MTT method at three different times (1, 15 and 24 h), and different concentrations of lupane (0.3, 0.7, 1.5, 6, 3 and 12 μg/mL). The cell function was assessed by the production of TNF-α and IL-10 by PBMCs quantified by specific enzyme immunoassay (ELISA). The activity of topoisomerases was assayed by in vitro biological assays and in silico molecular docking.ResultsThe results obtained showed that lupane at concentrations below 1.5 μg/mL was not toxic to the cells. Moreover, lupane was not able to activate cellular functions and did not alter the production of IL-10 and TNF-α. Furthermore, the data showed that lupane has neither interfered in the action of topoisomerase I nor in the action of topoisomerase II.ConclusionBased on preclinical results obtained in this study, we highlight that the compound studied (lupane) has moderate cytotoxicity, does not induce the production of TNF-α and IL-10, and does not act on human topoisomerases. Based on the results of this study and taking into consideration the reports about the anti-inflammatory and leishmanicidal activity of 3β, 6β, 16β-trihydroxylup-20(29)-ene, we suggest that this compound may serve as a biotechnological tool for the treatment of leishmaniasis in the future.

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Section: Discussionmentioning

confidence: 99%

The effect of 3β, 6β, 16β-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells

Lacouth-Silva¹,

Xavier²,

Setúbal³

et al. 2015

BMC Complement Altern Med

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“…In our method, the dose increment in MCDIS was dependent on the initial dose. Some studies have used a constant dose increment but different magnitude of initial dose [ 24 , 25 ], and other studies have increased the dose with irregular increments [ 26 , 27 ]. In practice, the dose increments should be determined according to the pharmacological characteristics of the drug.…”

Section: Discussionmentioning

confidence: 99%

Use of a failure probability constraint to suggest an initial dose in a phase I cancer clinical trial

Chang¹,

Chang²,

Lin³

et al. 2014

Journal of Food and Drug Analysis

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The primary objective of a Phase I cancer clinical trial is to determine the maximum tolerated dose of a drug. The "failure probability" was proposed and used as a constraint to help identify a suitable initial dose range. The maximum tolerated dose was then determined based on a 3 + 3 cohort-based escalation scheme. Multiple simulations were conducted, and the method was evaluated according to the required sample size and accuracy and precision of maximum tolerated dose estimate. The results indicated that the median of the initial dose range suggested using a failure probability is a suitable initial dose regardless of the dose escalation sequence used for a cancer Phase I study. This initial dose required a smaller sample size and resulted in less bias of the estimated maximum tolerated dose compared with a commonly used initial dose, that is, 10% of the lethal dose. We tested our approach using real dose and toxicity outcome data from two published Phase I studies. These results indicate that adding a failure probability constraint into the calculation of the initial dose range will improve the efficiency of Phase I cancer trials.

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“…Beldner et al [ 19 ] conducted a phase I dose escalation study of vinorelbine and TPT combination therapy in patients with recurrent SCLC and NSCLC. The aim of this study was to evaluate the optimal dosage and the MTD of TPT and vinorelbine administered on an alternate dosing schedule.…”

Section: Phase I Clinical Trials Of Tpt As Combination Therapymentioning

confidence: 99%

“…In summary, phase I clinical trials done on TPT had shown good disease responses with minimal toxicity in combination with gemcitabine and vinorelbine at a dose range of 0.75 - 4 mg/m 2 /day given as infusion for 5 days every 3 weeks or as weekly bolus infusion for 3 weeks every 28 days [ 15 , 16 , 18 , 19 ]. TPT in combination with cisplatin is associated with high toxicity [ 14 ].…”

Section: Phase I Clinical Trials Of Tpt As Combination Therapymentioning

confidence: 99%

Role of Topotecan in Non-Small Cell Lung Cancer: A Review of Literature

2015

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Topotecan (TPT), a chemotherapeutic agent, is a topoisomerase-I inhibitor. Topoisomerase-I is a nuclear enzyme that relieves torsion strain in DNA by opening single strand breaks which helps in DNA replication. TPT inhibits this enzyme, thus preventing DNA replication and causes cell death. TPT has demonstrated to have broad spectrum of antitumor activity in tumors like cervical, ovarian, endometrial and small cell lung cancers (SCLCs). The intravenous (IV) formulation of the drug is currently approved by the US Food and Drug Administration for the treatment of patients with SCLC and ovarian cancer at a dose of 1.5 mg/m2 administered daily for five consecutive days, with treatment cycles repeated every 3 weeks. TPT has shown some promising activity in the treatment of non-small cell lung cancer (NSCLC) with favorable side effect profile. Several clinical trials have been conducted with TPT in either IV or oral formulation for the treatment of NSCLC as a first or second-line treatment. Here we reviewed all the clinical trials done with TPT to date in the treatment of NSCLC both as a single-agent and combination therapy.

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Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer

Cited by 5 publications

References 25 publications

The effect of 3β, 6β, 16β-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells

The effect of 3β, 6β, 16β-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells

Use of a failure probability constraint to suggest an initial dose in a phase I cancer clinical trial

Role of Topotecan in Non-Small Cell Lung Cancer: A Review of Literature

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