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Expert Opinion on Pharmacotherapy Mar 2010In spite of the recent progress, the prognosis of acute myelogenous leukemia (AML) remains poor, particularly in patients with relapsed disease and in the elderly. In... (Review)
Review
IMPORTANCE OF THE FIELD
In spite of the recent progress, the prognosis of acute myelogenous leukemia (AML) remains poor, particularly in patients with relapsed disease and in the elderly. In these situations, there is at present no standard of care, and new drugs are urgently needed.
AREAS COVERED IN THIS REVIEW
Preclinical and clinical studies of Laromustine (formerly cloretazine, VNP-40101M), a new sulfonylhydrazine alkylator, in AML published between 2000 and September 2009 are presented and discussed.
WHAT THE READER WILL GAIN
Mechanisms of action of Laromustine and preclincal data that support the rationale for its use in patients with AML are summarized. Laromustine has limited extramedullary toxicity. In Phase II studies, it produced 32% complete responses in elderly patients with previously untreated AML. In a Phase III comparative study of its combination with cytarabine in relapsed AML, increased response rate was offset by excessive toxicity.
TAKE HOME MESSAGE
Laromustine has significant activity in AML. As a single agent, laromustine may represent an alternative to conventional treatments for elderly patients. Although significant activity was seen, safety and optimal dosing in combination regimen remain to be established and are now being investigated.
Topics: Aged; Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Hydrazines; Leukemia, Myeloid, Acute; Remission Induction; Sulfonamides; Treatment Outcome
PubMed: 20163276
DOI: 10.1517/14656561003621232 -
Drug Metabolism and Disposition: the... Aug 2016This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of... (Review)
Review
This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of [(14)C]laromustine with rat, dog, monkey, and human liver microsomes produced eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because NADPH was not required for the formation of most components, which instead involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Liquid chromatography-multistage mass spectrometry (LC-MS(n)) studies determined that collision-induced dissociation, and not biotransformation or enzyme catalysis, produced the unique mass spectral rearrangement. Accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) significantly aided determination of the elemental compositions of the fragments and in the case of laromustine revealed the possibility of rearrangement. Further, collision-induced dissociation produced the loss of nitrogen (N2) and methylsulfonyl and methyl isocyanate moieties. The rearrangement, metabolite/decomposition products, and conjugation reactions were analyzed utilizing hydrogen-deuterium exchange, exact mass, (13)C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR), and LC-MS(n) experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. Such techniques produced valuable insights into these functions: 1) Cytochrome P450 is involved in C-7 formation but plays little or no role in the conversion of [(14)C]laromustine to C-1 through C-6 and C-8; 2) the relative abundance of individual degradation/metabolite products was not species-dependent; and 3) laromustine produces several reactive intermediates that may produce the toxicities seen in the clinical trials.
Topics: Animals; Antineoplastic Agents, Alkylating; Biotransformation; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Dogs; Haplorhini; Humans; Hydrazines; Hydroxylation; Microsomes, Liver; Molecular Structure; Rats; Substrate Specificity; Sulfonamides
PubMed: 27278961
DOI: 10.1124/dmd.116.069823 -
IDrugs : the Investigational Drugs... Jan 2009Laromustine (Onrigin), under development by Vion Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of alkylating agents and is in clinical development for the... (Review)
Review
Laromustine (Onrigin), under development by Vion Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of alkylating agents and is in clinical development for the treatment of malignancies. Laromustine is a prodrug that yields a chloroethylating compound (VNP-4090-CE) and a carbamoylating compound (methyl isocyanate). The antineoplastic effect of laromustine is attributed primarily to the chloroethylating species, which causes the preferential alkylation of DNA at the O6 position of guanine, a lesion that results in interstrand crosslinks and, eventually, cell death. The carbamoylating species contributes to antitumor activity by inhibiting the DNA repair protein O6-alkylguanine transferase. Early phase I clinical trials in patients with solid tumors indicated that laromustine was associated with myelosuppression; few extramedullary toxicities were observed, indicating potential efficacy for the treatment of hematological malignancies. Phase II trials have been completed in patients with previously untreated acute myelogenous leukemia (AML), high-risk myelodysplastic syndrome (MDS) and relapsed AML. The most encouraging results were observed in patients over 60 years of age with poor-risk de novo AML for which no standard treatment exists. Laromustine is currently in phase II/III trials for AML and phase II trials for MDS and solid tumors. Laromustine appears to be a promising agent that will add to the armamentarium of drugs available to treat patients who do not respond to, or are not fit for, intensive chemotherapy, such as elderly individuals.
Topics: Aged; Animals; Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Humans; Hydrazines; Isocyanates; Middle Aged; Neoplasms; Prodrugs; Sulfonamides
PubMed: 19127504
DOI: No ID Found -
Leukemia Research Aug 2009
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hydrazines; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 19328547
DOI: 10.1016/j.leukres.2009.02.002 -
International Journal of Radiation... Mar 2012These studies explored questions related to the potential use of Laromustine in the treatment of solid tumors and in combination with radiotherapy.
PURPOSE
These studies explored questions related to the potential use of Laromustine in the treatment of solid tumors and in combination with radiotherapy.
MATERIALS AND METHODS
The studies used mouse EMT6 cells (both parental and transfected with genes for O(6)-alkylguanine-DNA transferase [AGT]), repair-deficient human Fanconi Anemia C and Chinese hamster VC8 (BRCA2(-/-)) cells and corresponding control cells, and EMT6 tumors in mice assayed using cell survival and tumor growth assays.
RESULTS
Hypoxia during Laromustine treatment did not protect EMT6 cells or human fibroblasts from this agent. Rapidly proliferating EMT6 cells were more sensitive than quiescent cultures. EMT6 cells expressing mouse or human AGT, which removes O(6)-alkyl groups from DNA guanine, thereby protecting against G-C crosslink formation, increased resistance to Laromustine. Crosslink-repair-deficient Fanconi Anemia C and VC8 cells were hypersensitive to Laromustine, confirming the importance of crosslinks as lethal lesions. In vitro, Laromustine and radiation produced additive toxicities to EMT6 cells. Studies using tumor cell survival and tumor growth assays showed effects of regimens combining Laromustine and radiation that were compatible with additive or subadditive interactions.
CONCLUSIONS
The effects of Laromustine on solid tumors and with radiation are complex and are influenced by microenvironmental and proliferative heterogeneity within these malignancies.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Combined Modality Therapy; Cricetinae; DNA Repair; Humans; Hydrazines; Mammary Neoplasms, Animal; Mice; Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Radiation Tolerance; Sulfonamides; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 22111842
DOI: 10.3109/09553002.2012.638359 -
Chemical Biology & Drug Design Jan 2018Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short...
pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs.
Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl-based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells.
Topics: Animals; Antineoplastic Agents; Catalysis; Cell Line, Tumor; DNA; Drug Design; Female; Half-Life; Humans; Hydrazines; Hydrogen-Ion Concentration; Isocyanates; Leukemia; Mice; Prodrugs; Protein Carbamylation; Sulfonamides; Transplantation, Homologous
PubMed: 28636806
DOI: 10.1111/cbdd.13057 -
Molecular and Cellular Biochemistry Nov 2012The thioredoxin system facilitates proliferative processes in cells and is upregulated in many cancers. The activities of both thioredoxin (Trx) and its reductase (TrxR)...
The thioredoxin system facilitates proliferative processes in cells and is upregulated in many cancers. The activities of both thioredoxin (Trx) and its reductase (TrxR) are mediated by oxidation/reduction reactions among cysteine residues. A common target in preclinical anticancer research, TrxR is reported here to be significantly inhibited by the anticancer agent laromustine. This agent, which has been in clinical trials for acute myelogenous leukemia and glioblastoma multiforme, is understood to be cytotoxic principally via interstrand DNA crosslinking that originates from a 2-chloroethylating species generated upon activation in situ. The spontaneous decomposition of laromustine also yields methyl isocyanate, which readily carbamoylates thiols and primary amines. Purified rat liver TrxR was inhibited by laromustine with a clinically relevant IC(50) value of 4.65 μM. A derivative of laromustine that lacks carbamoylating activity did not appreciably inhibit TrxR while another derivative, lacking only the 2-chloroethylating activity, retained its inhibitory potency. Furthermore, in assays measuring TrxR activity in murine cell lysates, a similar pattern of inhibition among these compounds was observed. These data contrast with previous studies demonstrating that glutathione reductase, another enzyme that relies on cysteine-mediated redox chemistry, was not inhibited by methylcarbamoylating agents when measured in cell lysates. Mass spectrometry of laromustine-treated enzyme revealed significant carbamoylation of TrxR, albeit not on known catalytically active residues. However, there was no evidence of 2-chloroethylation anywhere on the protein. The inhibition of TrxR is likely to contribute to the cytotoxic, anticancer mechanism of action for laromustine.
Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Carbamates; Carmustine; Cell Line, Tumor; Cysteine; Drug Screening Assays, Antitumor; Hydrazines; Hydrogen-Ion Concentration; Isocyanates; Mice; Molecular Sequence Data; Peptides; Rats; Sulfonamides; Tandem Mass Spectrometry; Thioredoxin-Disulfide Reductase; Time Factors
PubMed: 22864532
DOI: 10.1007/s11010-012-1411-y -
Clinical Lymphoma, Myeloma & Leukemia Jun 2010Although alkylators are known to be effective against some myeloid leukemias, resistance is often mediated via O6-alkylguanine-DNA alkyltransferase (AGT). Temozolomide's...
PURPOSE
Although alkylators are known to be effective against some myeloid leukemias, resistance is often mediated via O6-alkylguanine-DNA alkyltransferase (AGT). Temozolomide's inhibition of AGT may sensitize leukemia cells to the novel alkylator laromustine. We conducted a phase I translational study to evaluate the toxicities and estimate the maximum tolerated dose (MTD) of laromustine when administered with temozolomide (TMZ) in patients with hematologic malignancies.
PATIENTS AND METHODS
TMZ was delivered twice daily for 5 doses followed by a single infusion of laromustine. The target TMZ dose was the dose that would reliably result in > 90% AGT depletion. Once the target TMZ dose was identified, the laromustine dose was escalated. A total of 35 patients with relapsed/refractory leukemia were treated.
RESULTS
Treatment with TMZ 300 mg for 5 doses resulted in > 90% depletion of AGT levels in 5 of 6 patients. The MTD of the combination was established at TMZ 1500 mg and laromustine 300 mg/m2. Three of the 7 patients assayed from cohort 1 achieved > 90% depletion of AGT activity (range, 77%-100% depletion; median, 88%). Five of 6 patients enrolled in cohort 2 achieved > 90% depletion of AGT activity (range, 92%-100% depletion; median, 93.5%). This established that the 300-mg dose of TMZ (1500 mg total) would be maintained in subsequent cohorts. The majority of adverse events were primarily hematologic, with infectious and pulmonary complications also noted. Three (9%) of the patients with previous refractory disease achieved a complete remission, and 5 (14%) of the patients achieved a morphologic, leukemia-free, but persistent hypocellular bone marrow status.
CONCLUSION
Laromustine in combination with TMZ is tolerable and manageable at doses that predictably suppress AGT. Reliable TMZ-induced inhibition of AGT was observed in doses that are clinically tolerable. Evidence of antitumor effect was observed with this combination, suggesting that further efficacy studies should be performed.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Female; History, 16th Century; Humans; Hydrazines; Leukemia; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; O(6)-Methylguanine-DNA Methyltransferase; Sulfonamides; Temozolomide; Young Adult
PubMed: 20511167
DOI: 10.3816/CLML.2010.n.033 -
Journal of Chromatographic Science Mar 2019The objective of this study was to validate a method for the determination of laromustine (VNP40101M) and short-lived its active metabolite (VNP4090CE) that has a...
The objective of this study was to validate a method for the determination of laromustine (VNP40101M) and short-lived its active metabolite (VNP4090CE) that has a half-life in human blood of <90 s in human plasma by liquid chromatography (LC) with tandem mass spectrometric (MS/MS) detection. We overcome the stability dilemma by acidified the human plasma with citric acid. Laromustine "breaks" down on the source of mass spectrometry to give m/z 249 which is the same m/z for VNP4090CE. Because VNP4090CE and laromustine elute at approximate retention time of 1.93 and 2.94 min, respectively, we were able to quantify both of them in one method. VNP40101M, VNP4090CE and the internal standards were extracted from human plasma by liquid-liquid extraction into ethyl ether. The ethyl ether layer was evaporated, reconstituted and analyzed using LC with MS/MS detection. Validation parameters such as selectivity, limit of quantitation, linearity, precision, accuracy, recovery, autosampler viability, freeze-thaw cycles and compounds stability are evaluated for this method. Results were calculated using peak area ratios, and calibration curves were generated using a weighted (1/x2) linear least-squares regression. Calibration curves for VNP40101M and VNP4090CE in human plasma ranged from 1.00 to 1,000 ng/mL. In this study, both intra- and inter-assay results demonstrated a relative standard deviation for calibration standards (inter-assay) and quality control samples (intra- and inter-assay) to be ≤15.0%. In this method, there is ~1.79% isotopic interference of VNP40101M to VNP40101M-IS, and ~3.76% isotopic interference of VNP4090CE to VNP4090CE-IS. It was concluded that there was no significant carryover.
Topics: Chromatography, Liquid; Humans; Hydrazines; Limit of Detection; Linear Models; Reproducibility of Results; Sulfonamides; Tandem Mass Spectrometry
PubMed: 30395213
DOI: 10.1093/chromsci/bmy100 -
Journal of Clinical Oncology : Official... Feb 2010PURPOSE An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously...
PURPOSE An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acute myeloid leukemia (AML). PATIENTS AND METHODS Laromustine 600 mg/m(2) was administered as a single 60-minute intravenous infusion. Patients were age 70 years or older or 60 years or older with at least one additional risk factor-unfavorable AML karyotype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or cardiac, pulmonary, or hepatic comorbidities. Results Eighty-five patients (median age, 72 years; range, 60 to 87 years) were treated. Poor-risk features included age 70 years or older, 78%; adverse karyotype, 47%; PS of 2, 41%; pulmonary disease, 77%; cardiac disease, 73%; and hepatic disease, 3%. Ninety-six percent of patients had at least two risk factors, and 39% had at least four risk factors. The overall response rate (ORR) was 32%, with 20 patients (23%) achieving complete response (CR) and seven (8%) achieving CR with incomplete platelet recovery (CRp). ORR was 20% in patients with adverse cytogenetics; 32% in those age 70 years or older; 32% in those with PS of 2; 32% in patients with baseline pulmonary dysfunction; 34% in patients with baseline cardiac dysfunction; and 27% in 33 patients with at least four risk factors. Twelve (14%) patients died within 30 days of receiving laromustine therapy. Median overall survival was 3.2 months, with a 1-year survival of 21%; the median duration of survival for those who achieved CR/CRp was 12.4 months, with a 1-year survival of 52%. CONCLUSION Laromustine has significant single-agent activity in elderly patients with poor-risk AML. Adverse events are predominantly myelosuppressive or respiratory. Response rates are consistent across a spectrum of poor-risk features.
Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Comorbidity; Europe; Female; Gene Expression Regulation, Leukemic; Heart Diseases; Humans; Hydrazines; Infusions, Intravenous; Kaplan-Meier Estimate; Karyotyping; Leukemia, Myeloid, Acute; Liver Diseases; Lung Diseases; Male; Middle Aged; Prospective Studies; Risk Assessment; Risk Factors; Sulfonamides; Treatment Outcome; United States
PubMed: 20026800
DOI: 10.1200/JCO.2009.24.2008