Clinical studies on triethylenephosphoramide and diethylenephosphoramide, compounds with nitrogen-mustard-like activity

Sykes, Marguerite P.; Karnofsky, David A.; Philips, Frederick S.; Burchenal, Joseph H.

doi:10.1002/1097-0142(195301)6:1<142::aid-cncr2820060114>3.0.co;2-w

Cited by 84 publications

(13 citation statements)

References 8 publications

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“…ThioTEPA (the IUPAC name: 1,1′,1′′‐phosphorothioyltriaziridine) is the anti‐cancer drug invented over 60 years ago3 which still remains important for practical application in medicine4–8 and physiology 9. Although this pharmaceutical compound is widely used, not only the physical properties of its molecule have not been studied carefully until recently,10,11 but even the mechanism of its action remains vague enough 5,8,12–15.…”

Section: Introductionmentioning

confidence: 99%

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

Nikolaienko

Bulavin

Sukhodub

2014

Molecular Informatics

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Non-covalent complexes of methylated nitrogenous DNA base guanine (m(9) Gua) with 1 to 6 molecules of anticancer drug ThioTEPA (1,1',1''-phosphorothioyltriaziridine) have been investigated by molecular modeling techniques (molecular docking and DFT geometry optimization), ab initio wavefunction calculations and the quantum theory of atoms in molecules (QTAIM). The accuracy of complex structures predicted by standard molecular docking techniques have been assessed by comparing them with ab initio calculations, and the most important differences have been discussed. Obtained stabilization enthalpies (kcal/mol) for the m(9) Gua⋅⋅⋅(ThioTEPA)n complexes with n=1…6 have been found to be -15.6, -26.5, -38.4, -49.6, -60.5 and -69.3 respectively. The non-covalent interactions revealed by the QTAIM method have been shown to be a dominating factor responsible for the complex stability, with hydrogen bonds of NH⋅⋅⋅N type being the most important interactions in small (n=1 to 4) and CH⋅⋅⋅N bonds - in large (n=5, 6) complexes. The obtained results may help to understand ThioTEPA-DNA interactions and clarify the mechanism of the drug action.

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Section: Introductionmentioning

confidence: 99%

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

Nikolaienko

Bulavin

Sukhodub

2014

Molecular Informatics

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“…Thiotepa is a derivative of N,N',N"-triethylenephosphoramide (TEPA) that was launched (1953) as immunosuppressive drug for transplantation in hematological diseases [73]. Subsequently, the drug was recommended for solid tumors in 1959 [74] and for breast cancer (0.3 to 0.4 mg/kg IV repeated every 1-4 weeks) in 1963 [75].…”

Section: Alkylating Agentsmentioning

confidence: 99%

Drug repurposing for breast cancer therapy: Old weapon for new battle

Aggarwal

Verma

Aggarwal

et al. 2021

Seminars in Cancer Biology

105

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Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process of drug repurposing. Repositioning approach not only fastens the process of drug development but also offers more effective, cheaper, safer drugs with lesser/known side effects. During the last decade, drugs such as alkylating agents, anthracyclins, antimetabolite, CDK4/6 inhibitor, aromatase inhibitor, mTOR inhibitor and mitotic inhibitors has been repositioned for breast cancer treatment. The repositioned drugs have been successfully used for the treatment of most aggressive triple negative breast cancer. The literature review suggest that serendipity plays a major role in the drug development. This article describes the comprehensive overview of the current scenario of drug repurposing for the breast cancer treatment. The strategies as well as several examples of repurposed drugs are provided. The challenges associated with drug repurposing are discussed. Current breast cancer therapyUnlike a decade ago, clinicians today have multiple choices for breast cancer treatment depending on the size, stage, grade, metastatic behavior, aggressiveness and intrinsic molecular subtyping of tumor, age, menopausal status, overall health, comorbidities, and preferences of the patient [9-13]. Chemotherapy, hormone therapy, immunotherapy, radiotherapy, and surgery are the common modalities for breast cancer [10,14]. Primary choice of treatment usually includes surgery with the aim of complete resection of the major tumor mass on the first hand. Breast conserving (lumpectomy) and breast reconstruction surgeries, mastectomy or lymph node dissections are performed initially in the breast cancer patients [15]. Surgery may be preceded with the systemic neoadjuvant therapies in order to shrink the tumor for effective surgery and to maximize breast conservation. For example, in HER2+ cases, Trastuzumab (Herceptin) and Pertuzumab (Perjeta)

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“…ThioTEPA (Figure 1) is an alkylating agent developed in the 1950s [1]. Interest in the drug was renewed with the finding that the dose can be increased dramatically when combined with peripheral blood progenitor cell or bone marrow transplantation.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high‐dose chemotherapy

Huitema¹,

Mathôt²,

Tibben³

et al. 2001

Brit J Clinical Pharma

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Aims To study the population pharmacokinetics of thioTEPA and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of thioTEPA (80±120 mg m x2 day x1 ), cyclophosphamide (1000±1500 mg m x2 day x1 ) and carboplatin (265±400 mg m x2 day x1 ) for 4 days. Methods ThioTEPA and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The in¯uence of patient characteristics on the pharmacokinetics was also determined. Results A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of thioTEPA (CL) was 34 l h x1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of thioTEPA was 47 l (IIV=7.5%; IOV=19%). The fraction of thioTEPA converted to TEPA divided by the volume of distribution of TEPA was 0.030 l x1 (IIV=39%; IOV=32%) and the elimination rate constant of TEPA was 0.64 h x1 (IIV=27%; IOV=32%). CL of thioTEPA was correlated with alkaline phosphatase and serum albumin. The volume of distribution of thioTEPA and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. Conclusions A model for the description of the pharmacokinetics of thioTEPA and TEPA was developed. Factors involved in the interpatient variability of thioTEPA and TEPA pharmacokinetics were identi®ed. Since, IOV of both thioTEPA and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.

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Clinical studies on triethylenephosphoramide and diethylenephosphoramide, compounds with nitrogen-mustard-like activity

Cited by 84 publications

References 8 publications

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

Drug repurposing for breast cancer therapy: Old weapon for new battle

Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high‐dose chemotherapy

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