3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Neoplasms

Currently, cancer and its progression to metastasis result in a large number of deaths. The lack of new drugs, appropriate clinical trials for metastasis preventive drugs and incomplete understanding of the molecular machinery are the major obstacles in metastasis prevention and treatment. On the other hand, thiosemicarbazones and their bioisosteres, thiazole and thiazolidinone are recurring in a wide range of biologically active compounds that reach different targets within tumor context and represent a promising start point to access potential candidates in metastatic cancer. Therefore, the search for new lead compounds showing highest anticancer potency and less adverse effects is the major challenger in drug discovery. The search was based from 1994 to 2018, focusing on thiosemicarbazone, thiazole and thiazolidinone cores that allowed us to discuss how the three multi-target motifs have been used for the target-based design and development of anticancer agents. In the lasts years, thiosemicarbazone, thiazole, and thiazolidinone cores are recurrent in many approaches for cancer therapy. In our search, it was verified that due to its biodiversity and versatility the anticancer potential of such structures has been assigned to distinct mechanisms reinforcing the value of these cores in the anticancer drug development. The present article aims point out the current application of thiosemicarbazone, thiazole and thiazolidinone cores in the design of anticancer agents within tumor progression, acting via varied targets such as cathepsins, NDRG1 gene and kinases, showing in vitro tests, in vivo tests and clinical trials. In our search it was possible to verify that thiazole is the most studied and the most important of the three structures. Therefore, we hope to provide new insights and valuable inspiration in the research of new drugs and development and contribute to the management of cancer.

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Disease Progression; Drug Delivery Systems; Drug Discovery; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; Thiazoles; Thiazolidines; Thiosemicarbazones

Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents.. Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors.. Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed.. The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Coordination Complexes; Gallium; Humans; Iron; Iron Chelating Agents; Molecular Mimicry; Neoplasms; Pyridines; Thiosemicarbazones

Targeting essential nutrients (eg., those required for DNA synthesis) to inhibit cancer cell growth is a well established therapeutic strategy. A good example is the highly successful folate antagonist, methotrexate. However, up until recently, strategies to target iron which is also crucial for DNA synthesis have not been systematically explored to develop agents for the treatment of cancer. Over the last 15 years, our laboratory has embarked upon structure-activity studies designed to develop novel Fe chelators with anti-cancer efficacy. These studies have led to the development of the dipyridyl thiosemicarbazone chelators that show potent and selective anti-cancer activity and which overcome resistance to other cytotoxic agents. This class of compounds include the chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which at optimal doses markedly inhibits tumour growth and is well tolerated. Moreover, this ligand does not induce overt Fe-depletion in vivo, probably because very low doses (0.4 mg/kg) are effective at inhibiting tumour growth. Importantly, our compounds are far more active and less toxic than the chelator, Triapine®, that is being assessed in a wide variety of international clinical trials. A vital part of the mechanism of action of these compounds is their ability to form a redox-active Fe complex that generates radicals to inhibit tumour growth. Due to their relatively high lipophilicity and low molecular weight of this class of compounds, oral activity may be expected in addition to their well known efficacy via the intravenous route.

Topics: Animals; Antineoplastic Agents; Biological Transport; Drug Design; Humans; Iron; Iron Chelating Agents; Molecular Structure; Neoplasms; Pyridines; Structure-Activity Relationship; Thiosemicarbazones; Treatment Outcome

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a highly-hydrophobic small molecule that was originally developed for cancer therapy (Triapine, Vion Pharmaceuticals) due to its ability to inhibit ribonucleotide reductase, a key enzyme required for DNA synthesis. 3-AP has a high affinity for divalent cations, chelating the Fe(2+) at the R2 subunit of the enzyme and inhibiting formation of a tyrosyl radical essential for ribonucleotide reduction. We have demonstrated that 3-AP is also a potent neuroprotectant (as such, it is referred to as "PAN-811"). In vitro it completely blocks ischemic neurotoxicity at a concentration of 0.5 microM (EC(50) approximate, equals 0.35 microM) and hypoxic toxicity at 1.2 microM (EC(50) approximate, equals 0.75 microM). Full protection of primary cortical and striatal neurons can be achieved with 3-AP when it is added to the medium at up to six hours after an ischemic insult. 3-AP also suppresses cell death induced by neurotoxic agents, including staurosporine, veratridine and glutamate, indicating activity against a central target(s) in the neurodegenerative process. 3-AP acts via neutralization of two important intracellular effectors of excitatory neurotoxicity; calcium and free radicals. Its reported ability to elevate anti-apoptotic proteins is likely to be a consequence of the suppression of excessive intracellular free calcium. In a rat model of transient ischemia, a single bolus delivery of 3-AP 1 h after the initiation of ischemic attack reduced infarct volume by 59% when administered i.c.v. (50 mug per rat) and by 35% when administered i.v. (1 mg/kg). In Phase I clinical trials in cancer therapy 3-AP had no cardiovascular, CNS or other major adverse effects. Thus, 3-AP has a high potential for development as a novel, potent neuroprotectant for the treatment of neurodegenerative diseases.

Topics: Analgesics; Animals; Brain Diseases; Cell Death; Humans; Neoplasms; Neurons; Neuroprotective Agents; Pyridines; Thiosemicarbazones

The importance of iron and copper in cancer biology has been well established. Iron plays a fundamental role in cellular proliferation and copper has been shown to be a significant cofactor for angiogenesis. Early observations with the chelator used for the treatment of iron overload, desferrioxamine, showed that it had promise as an anticancer agent. These results sparked great interest in the possibility of developing more effective iron chelators for cancer therapy. The recent entry into clinical trials of the iron-binding drug, Triapine, provides evidence of the potential of this antitumor strategy. Likewise, chelators originally designed to treat disorders of copper overload, such as penicillamine, trientine, and tetrathiomolybdate, have also emerged as potential anticancer drugs, as they are able to target the key angiogenic cofactor, copper. In this review, we will discuss the development of these and other chelators that show potential as anticancer agents.

Topics: Antineoplastic Agents; Chelating Agents; Deferoxamine; Humans; Neoplasms; Pyridines; Structure-Activity Relationship; Thiosemicarbazones

Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.. Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.. Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.. This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Gemcitabine; Humans; Leukopenia; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyridines; Ribonucleoside Diphosphate Reductase; Thiosemicarbazones; Thrombocytopenia

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.. Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated.. Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route.. Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biological Availability; California; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Pyridines; Thiosemicarbazones; Treatment Outcome

3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.. The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.. Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.. The MTD for this combination was 3-AP 60 mg/m(2) per day on days 1-3 and irinotecan 200 mg/m(2) on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Camptothecin; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Synergism; Female; Glucuronosyltransferase; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Polymorphism, Genetic; Pyridines; Thiosemicarbazones; Treatment Outcome

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin.. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment.. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyridines; Thiosemicarbazones

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer.. Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients.. Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m(2)/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m(2)/d but administered every 2 weeks. At 120 mg/m(2)/d, three of seven patients had dose-limiting but reversible asthenia, hyperbilirubinemia, and azotemia or acidosis; however, in the case of renal and hepatic adverse events, the events were related to pre-existing borderline abnormal organ function. Therefore, the recommended phase II dose for 3-AP administered by 96-hour IV infusion is 120 mg/m(2)/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg/m(2), with substantial inter-patient variability. There was no correlation between dose and clearance (R(2) = 0.0137). There were no objective responses, but there was prolonged stabilization of disease or decreases in serum tumor markers associated with stable disease in four patients.. The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.

Topics: Adult; Aged; Asthenia; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Hyperbilirubinemia; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prospective Studies; Pyridines; Risk Factors; Thiosemicarbazones; Uremia

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer.. 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m(2). Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m(2) in cohorts of three to six patients. Following the gemcitabine 1000 mg/m(2) dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m(2).. 3-AP at 105 mg/m(2) administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m(2) produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m(2) administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis.. 3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Male; Methemoglobinemia; Middle Aged; Neoplasms; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones

Topics: Antineoplastic Agents; DNA Replication; DNA, Neoplasm; Humans; Neoplasms; Pyridines; Thiosemicarbazones

A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase.. Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m(2)/day, but was reduced to 2 mg/m(2)/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3-6 patients. After the 12 mg/m(2)/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m(2)/day, the study was amended to determine the safety and tolerability of the 96-mg/m(2) dose administered daily for 5 days every 2 weeks in an expanded cohort of patients.. A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2-4 drug-related adverse events were first observed at a dose of 96 mg/m(2)/day. Grade 3-4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m(2) dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1-2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3-4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m(2)/day dose averaged 8 microM, and the mean elimination T(1/2) ranged from 35 min to 3 h, with a median value of approximately 1 h. Cumulative urinary recovery averaged 1-3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed.. Triapine administered at a dose of 96 mg/m(2) by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of ribonucleotide reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asthenia; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones

To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m(2) with escalation based on a modified Fibonacci scheme.. A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m(2) to 105 mg/m(2). Blood and urine samples were collected and 3-AP was measured by HPLC.. A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade l occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease.. Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m(2) on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.

Topics: Adult; Aged; Anemia; Blood Coagulation Disorders; Dose-Response Relationship, Drug; Female; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Pyridines; Thiosemicarbazones; Thrombocytopenia

To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study.. Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC-MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC-MS/MS monitoring of CYP specific metabolite formation.. Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity.. CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug-drug interactions.

Topics: Cells, Cultured; Chemoradiotherapy; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inducers; Drug Evaluation, Preclinical; Drug Interactions; Emtricitabine; Hepatocytes; Humans; Inactivation, Metabolic; Microsomes, Liver; Neoplasms; Primary Cell Culture; Pyridines; Radiation-Sensitizing Agents; Tandem Mass Spectrometry; Tenofovir; Thiosemicarbazones

Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN-811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811·Cl·H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5-FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment.

Topics: Animals; Cell Line, Tumor; Cognition Disorders; Humans; Mice; Neoplasms; Neurotoxicity Syndromes; Pyridines; Reactive Oxygen Species; Thiosemicarbazones

The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates.. A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system.. 3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study.. This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.

Topics: Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood; Body Surface Area; Clinical Trials, Phase I as Topic; Computer Simulation; Erythrocytes; Female; Genotype; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Models, Statistical; Neoplasms; Pyridines; Sex Characteristics; Thiosemicarbazones

Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine(R), NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G(1)/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes that rely on deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of human cancers.

Topics: Base Sequence; Blotting, Western; Cell Line; DNA Damage; DNA Primers; DNA Repair; Flow Cytometry; Gene Silencing; Humans; Neoplasms; Pyridines; Radiation Tolerance; Ribonucleotide Reductases; Thiosemicarbazones; Tumor Suppressor Protein p53

The metal chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase. EPR spectra consistent with signals from Fe-transferrin, heme, and low-spin iron or cupric ion were observed in peripheral blood mononuclear cells (PBMCs) obtained from patients treated with Triapine. One signal that is unequivocally identified is the signal for Fe-transferrin. It is hypothesized that Fe uptake is blocked by reactive oxygen species generated by FeT(2) or CuT that damage transferrin or transferrin receptor. A potential source for the increase in the heme signal is cytochrome c released from the mitochondria. These results provide valuable insight into the in vivo mechanism of action of Triapine.

Topics: Cytochromes c; Electron Spin Resonance Spectroscopy; Humans; Monocytes; Neoplasms; Pyridines; Thiosemicarbazones

Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established therapies. Iron (Fe) is critical for cell-cycle progression and DNA synthesis and potentially represents a novel molecular target for the design of new anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe chelators using human tumors. In this investigation, the ligands showed broad antitumor activity and could overcome resistance to established antitumor agents. The in vivo efficacy of the most effective chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT- and vehicle-treated mice, probably because of the very low doses required to induce anticancer activity. Dp44mT caused up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 in the tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action.

Topics: Animals; Antineoplastic Agents; Blood Cells; Cell Line, Tumor; Cell Proliferation; Chelation Therapy; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Iron; Iron Chelating Agents; Liver; Mice; Mice, Nude; Myocardium; Neoplasms; Organ Size; Pyridines; Spleen; Thiosemicarbazones; Transplantation, Heterologous; Tumor Stem Cell Assay; Tumor Suppressor Protein p53

Topics: Cell Cycle; Clinical Trials as Topic; DNA Damage; Drug Administration Schedule; Enzyme Inhibitors; Humans; Neoplasms; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones