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Dactinomycin

"A compound composed of a two CYCLIC PEPTIDES attached to a phenoxazine that is derived from STREPTOMYCES parvullus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. (From AMA Drug Evaluations Annual, 1993, p2015)" (MeSH 2013)

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Lertkhachonsuk R, Wairachpanich V
Treatment Outcomes of Gestational Trophoblastic Neoplasia in King Chulalongkorn Memorial Hospital over Two Decades.
J Reprod Med. 2016 May-Jun; 61(5-6):238-42 [PubMed] Related Publications
OBJECTIVE: To evaluate changes in treatment outcomes and epidemiologic profiles of gestational trophoblastic neoplasia (GTN) patients over a 20-year period.
STUDY DESIGN: This retrospective study recruited all GTN patients who were treated at King Chulalongkorn Memorial Hospital during the period January 1994-December 2013. Clinical data were collected. Statistical analyses were performed, with p values < 0.05 considered statistically significant.
RESULTS: There were 183 GTN cases during the study period, resulting in an incidence of 1.03 cases per 1,000 deliveries. Fifty-five cases (30.1%) were diagnosed as GTN following nonmolar pregnancy, and 128 cases were identified as postmolar GTN. A total of 113 cases were diagnosed as stage I, 12 as stage II, 40 as stage III, and 17 as stage IV; 125 cases (68.3%) were clas- sified as low risk, and 57 cases (31.1%) as high risk. Actinomycin D was the most frequently used first-line single-agent chemotherapy (98 cases), and VAC regimen was the most frequently used combination chemotherapy (24 cases). EMACO regimen was the most frequently used second-line chemotherapy (11 cases). The median number of chemotherapy courses was 4.5 courses in the first decade and 6 courses in the second decade of our study (p = 0.005). Median duration of treatment was 72 days (range, 7-491 days). Overall remission rate was 82.6%, with rates of 76% in the first decade and 90.8% in the second decade of the study (p=0.03).
CONCLUSION: Incidence of high-risk GTN increased over the course of the study period at our national referral hospital. Improvement in patient outcomes was observed, being directly associated with improved targeted chemotherapy regimens.

Lertkhachonsuk AA, Hanvoravongchai P
Comparison of Cost-Effectiveness Between Actinomycin D Versus Methotrexate-Folinic Acid in the Treatment of Low-Risk Gestational Trophoblastic Neoplasia.
J Reprod Med. 2016 May-Jun; 61(5-6):230-4 [PubMed] Related Publications
OBJECTIVE: To compare the cost-effectiveness between actinomycin D (Act-D) and methotrexate-folinic acid (MTX-FA) in the treatment of low-risk gestational trophoblastic neoplasia (GTN) in the Thai population.
STUDY DESIGN: A comparative cost-effectiveness analysis was performed from a societal perspective. A decision tree model was developed comparing 2 alternative treatment options: initial 5-day Act-D and 8-day MTX-FA. Treatment would be switched to another regimen in case of resistance. The outcome of interest is number of days to remission. Clinical data was obtained from our previous study in which Act-D demonstrated 100% remission rates as compared to 73.6% for MTX-FA. Cost of treatment data, which includes chemotherapeutics, accessory medications, laboratory tests, and hospital fees, was obtained from a university hospital. Patient-related travel cost and opportunity cost due to absence from work were also included. All costs were calculated to 2015 base year.
RESULT: Costs per treatment cycle were $308.01 and $227.20 US dollars (USD) for 5-day Act-D and 8-day MTX-FA, respectively. Expected time toward treatment completion for Act-D was 12.6 days shorter than for MTX-FA. Expected costs toward remission for initial treatment with Act-D and MTX-FA were $1,078.04 and $1,064.56 USD, respectively, i.e., an incremental cost effectiveness ratio (ICER) of $1.07 USD/day of earlier treatment completion. After sensitivity analysis, remission rate of lower than 72% would make initial treatment with MTX-FA more expensive than with Act-D.
CONCLUSION: Treatment costs of low-risk GTN are almost equal between the 2 treatment options with different time to remission. Initial treatment with MTX-FA is slightly less expensive, but there is longer time to remission. The ICER of initial treatment with Act-D over MTX-FA is $1.07 USD/day of earlier treatment completion.

Lawrie TA, Alazzam M, Tidy J, et al.
First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2016; (6):CD007102 [PubMed] Related Publications
BACKGROUND: This is the second update of a Cochrane review that was first published in 2009, Issue 1, . Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear.
OBJECTIVES: To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN.
SEARCH METHODS: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase in September 2008, February 2012, and January 2016. In addition, we searched online trial registers for protocols and ongoing trials.
SELECTION CRITERIA: For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated versions of the review, we included only RCTs.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed using the random-effects model.
MAIN RESULTS: We included seven RCTs (667 women) in this updated review. Most studies were at a low or moderate risk of bias and all compared methotrexate with actinomycin D. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) actinomycin D (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV actinomycin D (75 women), one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV actinomycin D (49 women), and one study compared eight-day IM MTX-FA with bi-weekly pulsed IV actinomycin D. One study contributed no data. Moderate-certainty evidence indicates that actinomycin D is probably more likely to lead to primary cure than methotrexate (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.57 to 0.75; six trials, 577 participants; I(2) = 26%), and first-line methotrexate treatment is probably more likely to fail than actinomycin D treatment (RR 3.55, 95% CI 1.81 to 6.95; six trials, 577 participants; I(2) = 61%; moderate-certainty evidence) Low-certainty evidence suggests that there may be little or no difference between methotrexate and actinomycin D treatment with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too inconsistent to be conclusive. Low-certainty evidence suggests that there may be little or no difference in the risk of severe adverse events (SAEs) between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%); however, the direction of effect favours methotrexate and more evidence is needed. Furthermore, evidence from subgroup analyses suggests that actinomycin D may be associated with a greater risk of SAEs than methotrexate (low-certainty evidence). We found no evidence on the effect of these treatments on future fertility.
AUTHORS' CONCLUSIONS: Actinomycin D is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, than a methotrexate regimen. There may be little or no difference between the pulsed actinomycin D regimen and the methotrexate regimen with regard to side-effects. However, actinomycin D may be associated with a greater risk of severe adverse events (SAEs) than a methotrexate regimen. Higher-certainty evidence is still needed on treating low-risk GTN and the four ongoing trials are likely to make a significant contribution to this field. Given the variety of treatment regimens, findings from these trials could facilitate a network meta-analysis in the next version of this review to help women and clinicians determine the best treatment options for low-risk GTN.

Mikami Y, Nagai T, Gomi Y, et al.
Methotrexate and actinomycin D chemotherapy in a patient with porphyria: a case report.
J Med Case Rep. 2016; 10:9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite their broadly recommended use as chemotherapeutic agents, the porphyrogenicity of methotrexate and actinomycin D have not been confirmed. Accordingly, it is not known whether these agents are safe for use in patients with porphyria.
CASE PRESENTATION: In this report, we present a case of an invasive mole with lung metastasis in a 49-year-old Japanese woman who had previously been diagnosed with acute intermittent porphyria at 27 years of age but had no recent history of acute intermittent porphyria attacks. Her serum human chorionic gonadotropin level was elevated 1 month after hysterectomy, and she was referred to our center for chemotherapy. After she received 100 mg of methotrexate, drug eruptions were observed starting on day 3 and grew progressively worse. Erythema and mucosal erosion spread throughout her body, whereupon she was administered prednisolone. In addition, our patient experienced febrile neutropenia and required granulocyte colony- stimulating factor treatment. No changes in our patient's urinary coproporphyrin or uroporphyrin levels were detected during this entire episode. Methotrexate was replaced by actinomycin D (0.5 mg/body intravenously on days 1-5 every 2 weeks). After five uneventful cycles of actinomycin D, our patient achieved and maintained a normal serum human chorionic gonadotropin level for 3 years.
CONCLUSIONS: Methotrexate and actinomycin D did not induce acute porphyric attacks in this patient with acute intermittent porphyria; however, severe adverse effects were noted with methotrexate. Although further investigation is required, our data suggest that these agents are nonporphyrinogenic and can therefore be used to treat patients with comorbid porphyria.

Walsh C, Bonner JJ, Johnson TN, et al.
Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.
Br J Clin Pharmacol. 2016; 81(5):989-98 [PubMed] Free Access to Full Article Related Publications
AIMS: Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses.
METHODS: Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48.
RESULTS: The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.
CONCLUSIONS: The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.

Liu J, Xie S, Wu Y, et al.
Apoptosis of human prostate cancer cells induced by marine actinomycin X2 through the mTOR pathway compounded by MiRNA144.
Anticancer Drugs. 2016; 27(3):156-63 [PubMed] Related Publications
The present study aimed to determine whether actinomycin X2 (AX2) intercepted the mTOR/PTEN/PI3K/Akt signaling pathway to inhibit human prostate cancer cells (PC-3) in vitro. The effects of AX2 on mTOR, PTEN, PI3K, and Akt at the protein level and mRNA were determined by western blotting and real-time reverse transcription-PCR (RT-PCR), respectively. Concurrently, the effects of AX2 on expression levels of MiRNA144 and MiRNA126 in PC-3 were measured by real-time RT-PCR. The association of MiRNA144 with 3'-UTR of mTOR was identified using the Dual-Luciferase Reporter Gene System. The direct effect of MIRNA144 on the mTOR/PTEN/PI3K/Akt pathway was determined by real-time RT-PCR and western blotting. Apoptosis of PC-3 cells induced by AX2 was determined by MTT and flow cytometry. The results indicated that mTOR/PTEN/PI3K/Akt were decreased and PTEN was increased by AX (1, 10 µmol/l) at protein and mRNA levels in a dose-dependent manner. MiRNA144 was decreased, whereas MiRNA126 was increased by AX2. MiRNA144 associated with 3'-UTR of mTOR was corroborated. Overexpression of MiRNA144 decreased mTOR, but did not affect PTEN, PI3K, or Akt. The proliferation rates of AX2 on PC-3 cells were decreased. It suggests that AX2 induces apoptosis of PC-3 cells via meddling in the mTOR/PTEN/PI3K/Akt signaling pathway, but those effects are compounded by MiRNA144. Both AX2 and MiRNA144 intercept the signaling in different ways but cross on mTOR.

Peng M, Ding Y, Yu L, et al.
Tegafur Substitution for 5-Fu in Combination with Actinomycin D to Treat Gestational Trophoblastic Neoplasm.
PLoS One. 2015; 10(11):e0143531 [PubMed] Free Access to Full Article Related Publications
Although 5-fluorouracil (5-Fu) combination chemotherapy provides a satisfactory therapeutic response in patients with gestational trophoblastic neoplasms (GTNs), it has severe side effects. The current study analyzed the therapeutic effects and side effects of tegafur plus actinomycin D (Act-D) vs. 5-Fu plus Act-D for the treatment of GTNs based on controlled historical records. A total of 427 GTN cases that received tegafur and Act-D combination chemotherapy at the Second Xiangya Hospital of XiangYa Medical School between August 2003 and July 2013 were analyzed based on historical data. A total of 393 GTN cases that received 5-Fu plus Act-D between August 1993 and July 2003 at the same hospital were also analyzed, which constituted the control group. The therapeutic effects, toxicity and side effects after chemotherapy were compared between the groups. The overall response rate was 90.63% in the tegafur+Act-D group (tegafur group) and 92.37% in the 5-Fu+Act-D group (5-Fu group); these rates were not significantly different (P > 0.05). However, the incidence rates of myelosuppression (white blood cell decline), gastrointestinal reactions (nausea, vomiting, dental ulcer, and diarrhea), skin lesions and phlebitis were lower in the tegafur group than in the 5-Fu group (P < 0.05). The results of this study may provide useful data for the clinical application of tegafur in GTN treatment.

You B, Deng W, Hénin E, et al.
Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial.
Int J Gynecol Cancer. 2016; 26(1):208-15 [PubMed] Related Publications
OBJECTIVES: In low-risk gestational trophoblastic neoplasia, chemotherapy effect is monitored and adjusted with serum human chorionic gonadotrophin (hCG) levels. Mathematical modeling of hCG kinetics may allow prediction of methotrexate (MTX) resistance, with production parameter "hCGres." This approach was evaluated using the GOG-174 (NRG Oncology/Gynecologic Oncology Group-174) trial database, in which weekly MTX (arm 1) was compared with dactinomycin (arm 2).
METHODS: Database (210 patients, including 78 with resistance) was split into 2 sets. A 126-patient training set was initially used to estimate model parameters. Patient hCG kinetics from days 7 to 45 were fit to: [hCG(time)] = hCG7 * exp(-k * time) + hCGres, where hCGres is residual hCG tumor production, hCG7 is the initial hCG level, and k is the elimination rate constant. Receiver operating characteristic (ROC) analyses defined putative hCGRes predictor of resistance. An 84-patient test set was used to assess prediction validity.
RESULTS: The hCGres was predictive of outcome in both arms, with no impact of treatment arm on unexplained variability of kinetic parameter estimates. The best hCGres cutoffs to discriminate resistant versus sensitive patients were 7.7 and 74.0 IU/L in arms 1 and 2, respectively. By combining them, 2 predictive groups were defined (ROC area under the curve, 0.82; sensitivity, 93.8%; specificity, 70.5%). The predictive value of hCGres-based groups regarding resistance was reproducible in test set (ROC area under the curve, 0.81; sensitivity, 88.9%; specificity, 73.1%). Both hCGres and treatment arm were associated with resistance by logistic regression analysis.
CONCLUSIONS: The early predictive value of the modeled kinetic parameter hCGres regarding resistance seems promising in the GOG-174 study. This is the second positive evaluation of this approach. Prospective validation is warranted.

Brodská B, Holoubek A, Otevřelová P, Kuželová K
Low-Dose Actinomycin-D Induces Redistribution of Wild-Type and Mutated Nucleophosmin Followed by Cell Death in Leukemic Cells.
J Cell Biochem. 2016; 117(6):1319-29 [PubMed] Related Publications
Specific mutations involving C-terminal part of the nucleolar protein nucleophosmin (NPM) are associated with better outcome of acute myeloid leukemia (AML) therapy, possibly due to aberrant cytoplasmic NPM localization facilitating induction of anti-NPM immune response. Actinomycin D (actD) is known to induce nucleolar stress leading to redistribution of many nucleolar proteins, including NPM. We analyzed the distribution of both wild-type and mutated NPM (NPMmut) in human cell lines, before and after low-dose actD treatment, in living cells expressing exogenous fluorescently labeled proteins as well as using immunofluorescence staining of endogenous proteins in fixed cells. The wild-type NPM form is prevalently nucleolar in intact cells and relocalizes mainly to the nucleoplasm following actD addition. The mutated NPM form is found both in the nucleoli and in the cytoplasm of untreated cells. ActD treatment leads to a marked increase in NPMmut amount in the nucleoplasm while a mild decrease is observed in the cytoplasm. Cell death was induced by low-dose actD in all the studied leukemic cell lines with different p53 and NPM status. In cells expressing the tumor suppresor p53 (CML-T1, OCI-AML3), cell cycle arrest in G1/G0 phase was followed by p53-dependent apoptosis while in p53-null HL60 cells, transient G2/M-phase arrest was followed by cell necrosis. We conclude that although actD does not increase NPM concentration in the cytoplasm, it could improve the effect of standard chemotherapy in leukemias through more general mechanisms.

Zajkowicz A, Gdowicz-Kłosok A, Krześniak M, et al.
Actinomycin D and nutlin-3a synergistically promote phosphorylation of p53 on serine 46 in cancer cell lines of different origin.
Cell Signal. 2015; 27(9):1677-87 [PubMed] Related Publications
The p53 tumor suppressor protein is a transcription factor activated by phosphorylation of its N-terminus. MDM2, encoded by a p53-activated gene, acts as a negative-feedback regulator of p53 by promoting p53 degradation. Moreover, MDM2 inhibits p53 by binding to and concealing its N-terminal transcription-activating domain. p53 can be activated by nutlin-3a, a molecule designed to bind MDM2 and prevent its interaction with p53. Actinomycin D promotes phosphorylation and accumulation of p53 via a mechanism that involves high expression of MDM2. We hypothesized that co-treatment of cells with actinomycin D and nutlin-3a would lead to synergistic activation of p53 by stimulating kinases and preventing accumulated MDM2 from binding to p53. Indeed, co-treatment of various cell lines with actinomycin D and nutlin-3a resulted in a synergistic increase of p53 phosphorylation on serine 46. We focused on this residue because it is a marker of the highest level of p53 activation. Co-treatment was associated with conspicuous decrease in a marker of mTOR activity in NCI-H28 cells and very strong activation of p53 targets, including CDKN1A and PML, in A549 cells. Other p53 target genes (SESN1, SESN2, TIGAR, DRAM1) were also efficiently upregulated; however, a marker of apoptosis (active caspase-3) appeared only in some cancer cell lines (e.g., A375 and other cell lines derived from melanoma) indicating that phosphorylation of p53 on serine 46 is not straightforwardly associated with induction of apoptosis. Moreover, our data suggest that melanoma may be a suitable target for drug combination used in this study.

Muilenburg DJ, Beasley GM, Thompson ZJ, et al.
Burden of disease predicts response to isolated limb infusion with melphalan and actinomycin D in melanoma.
Ann Surg Oncol. 2015; 22(2):482-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Isolated limb infusion (ILI) with melphalan is a minimally invasive, effective treatment for in transit melanoma. We hypothesized that burden of disease (BOD) would correlate to treatment response.
METHODS: We retrospectively analyzed a prospectively collected database from two academic centers. BOD was stratified as high or low (low ≤ 10 lesions, none >2 cm). Response rates were measured 3 months post-ILI. Multivariable analysis (MV) was used to evaluate the association between the response and BOD. Kaplan-Meier methods with log-rank tests and MV Cox proportional hazard models were used to analyze overall survival (OS) and progression free survival (PFS).
RESULTS: Sixty (38 %) patients had low and 100 (62 %) high BOD. Patients with low BOD had an overall response rate (ORR) of 73 % with 50 % CR, compared with an ORR of 47 % with 24 % CR in patients with high BOD (p = 0.002). MV analysis of preoperative, intraoperative, and postoperative parameters showed no significant impact on 3-month response. Patients with a CR at 3 months demonstrated improved PFS over the remainder of the cohort, but OS was similar. Low BOD patients had an increased median PFS of 6.9 versus 3.8 months (p = 0.047) and a increased median OS of 38.4 versus 30.9 months (p = 0.146).
CONCLUSIONS: Lower BOD is associated with an increased ORR and CR rate with statistically significantly improved PFS in patients undergoing ILI for in transit extremity melanoma. BOD provides useful prognostic information for patient counseling and serves as a marker to stratify patient risk groups.

Hill CR, Cole M, Errington J, et al.
Characterisation of the clinical pharmacokinetics of actinomycin D and the influence of ABCB1 pharmacogenetic variation on actinomycin D disposition in children with cancer.
Clin Pharmacokinet. 2014; 53(8):741-51 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVE: Despite its important role in cancer treatment, there is currently very limited available information concerning the clinical pharmacology of actinomycin D (Act D). The study was designed to characterise Act D pharmacokinetics and investigate the impact of pharmacogenetic variation on Act D disposition in children with cancer.
METHODS: A total of 650 plasma samples collected over an 8 year period from 117 patients ≤21 years receiving Act D (0.4-1.6 mg/m(2)) were used to characterise a population pharmacokinetic model. Polymorphisms in ABCB1 were analysed in 140 patients.
RESULTS: A 3-compartment model provided a good fit to the data. Median values for Act D clearance and volume of distribution in the central compartment (V 1) obtained from the model were 5.3 L/h and 1.9 L (13.9 L/h/70 kg and 7.5 L/70 kg), respectively. There was substantial inter-subject variation in all pharmacokinetic parameters (coefficients of variation 53-81 % for non-normalised values). Body weight was a major determinant of Act D clearance, such that dose capping at 2 mg in larger children at a protocol dose of 1.5 mg/m(2) resulted in significantly lower area under the plasma concentration-time curves (mean AUC values: 9.3 versus 12.8 mg·min/L; P < 0.0001). No significant relationships were found between ABCB1 genetic variants and Act D pharmacokinetic parameters, nor between CL, V 1 or dose and incidence of grade 3 or 4 toxicity.
CONCLUSION: We have defined the pharmacokinetics of Act D in a paediatric patient population, providing robust estimates of key pharmacokinetic parameters. Pharmacokinetic data bring into question the current clinical practice of dose capping at 2 mg in larger patients. Pharmacogenetic variation in candidate drug transporter genes identified from preclinical studies does not significantly impact on Act D exposure in a clinical setting.

Krześniak M, Zajkowicz A, Matuszczyk I, Rusin M
Rapamycin prevents strong phosphorylation of p53 on serine 46 and attenuates activation of the p53 pathway in A549 lung cancer cells exposed to actinomycin D.
Mech Ageing Dev. 2014; 139:11-21 [PubMed] Related Publications
The activation of the p53 pathway by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a molecule that mimics metabolic stress, is attenuated by rapamycin, an inhibitor of mTOR kinase, immunosuppressant, and cancer drug. Rapamycin also extends lifespan in experimental animals. Because AICAR is a relatively weak activator of p53, we investigated whether stimulation of p53 by the strong activator actinomycin D is also sensitive to the inhibitory effect of rapamycin. In A549 lung cancer cells, activation of p53 by actinomycin D was associated with phosphorylation of p53 on Ser46. Rapamycin inhibited the accumulation of phospho-Ser46 p53, attenuated upregulation of some p53 target genes, and altered cell-cycle progression. Moreover, in cells exposed to actinomycin D, rapamycin attenuated the accumulation of PML, a protein that in some conditions stimulates Ser46 phosphorylation. However, Ser46 phosphorylation was not diminished in PML-knockdown cells, suggesting that in our system PML does not play a major role in stimulating p53 phosphorylation on Ser46. Knockdown of p53 diminished the upregulation of PML by stress-inducing agents, consistent with the idea that PML is a p53-regulated gene. Our data suggest that the attenuation of p53 phosphorylation on Ser46 may play a significant role in the biological activity of anti-aging rapamycin.

Baskin Y, Amirfallah A, Calibasi G, Olgun N
Hepatopathy-Thrombocytopenia Syndrome During Actinomycin D Treatment May Be Related to MDR1 (ABCB1) Gene Polymorphisms.
Am J Ther. 2016 Mar-Apr; 23(2):e594-6 [PubMed] Related Publications
The antitumor agent actinomycin D has been used in the treatment of Wilms tumor for the past 40 years. Actinomycin D-induced hepatopathy-thrombocytopenia syndrome (HTS) is characterized as a rare syndrome. The mechanism underlying HTS may differ with individual multidrug resistance protein-1 (MDR1) genotype. The relationship between actinomycin D-related HTS and MDR1 gene mutations is presented in this case study of a pediatric patient with Wilms tumor. Our findings revealed that the girl had (-)1G>A, 1236C>T, 2677G>T, 3435C>T, and 61A>G MDR1 gene mutations. Understanding the function of genetic variants of MDR1 is an important aim for personalized cancer management.

Rao B, Lain S, Thompson AM
p53-Based cyclotherapy: exploiting the 'guardian of the genome' to protect normal cells from cytotoxic therapy.
Br J Cancer. 2013; 109(12):2954-8 [PubMed] Free Access to Full Article Related Publications
Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic effect of p53 can protect normal cells from the toxicity of S- or M-phase poisons. Here, we have reviewed existing cyclotherapy regimens using two well-known p53 activators, nutlin-3 and actinomycin D. We have highlighted an exemplar clinical perspective for cyclotherapy in breast cancer. The recent development of novel stapled peptides as activators of p53 without the corresponding cytotoxicity holds great promise for cyclotherapy to enhance the therapeutic window of existing chemotherapy drugs.

Martín-Lázaro JF, Palanca D, Garcia-Iñiguez JP, et al.
Hepatopathy-thrombocytopenia syndrome after actinomycin-D therapy: treatment with defibrotide.
Pediatr Hematol Oncol. 2013; 30(1):25-7 [PubMed] Related Publications
We report a case of administration compassionate use defibrotide in a 13-year-old girl with Sinusoidal Obstructive Syndrome and thrombocytopenia, also known as Hepatopathy--Thrombocytopenia Syndrome (HTS) during chemotherapy for Wilms' tumor.

Wang SY, Lee AY, Lee YL, et al.
Spermine attenuates the action of the DNA intercalator, actinomycin D, on DNA binding and the inhibition of transcription and DNA replication.
PLoS One. 2012; 7(11):e47101 [PubMed] Free Access to Full Article Related Publications
The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular) are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD) as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone) (MGBG) enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion.

Fu J, Fang F, Xie L, et al.
Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2012; 10:CD007289 [PubMed] Related Publications
BACKGROUND: Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear.
OBJECTIVES: To systematically review the evidence for the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy.
SEARCH METHODS: We performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and EMBASE (1980 to week 9, 2012). The search strategy was developed using free text and medical subject headings (MESH). We handsearched reference lists of relevant literature to identify additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of P-Chem for HM.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and extracted data using a specifically designed data collection form. Meta-analyses were performed by pooling data from individual trials using RevMan 5.1 software.
MAIN RESULTS: We included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality.P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; RR 0.37; 95% confidence interval (CI) 0.24 to 0.57; I(2) = 0%; P < 0.00001), However, owing to the poor quality of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28; 95% CI 0.10 to 0.73; P = 0.01), therefore we consider this evidence to be of a low quality.The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72; 95% CI 13.19 to 44.24; P = 0.0003) and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10; 95% CI 0.52 to 1.68; P = 0.0002). We consider this evidence to be of a low to very low quality for similar reasons to those listed above.There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes.
AUTHORS' CONCLUSIONS: P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delay treatment of GTN and expose women unnecessarily to toxic side effects, this practice cannot currently be recommended.

Baptista AM, Belfort P
Comparison of methotrexate, actinomycin D, and etoposide for treating low-risk gestational trophoblastic neoplasia.
Int J Gynaecol Obstet. 2012; 119(1):35-8 [PubMed] Related Publications
OBJECTIVE: To compare the efficacy and toxicity of 3 single agent chemotherapeutic regimens in low-risk gestational trophoblastic neoplasia (LRGTN).
METHODS: A prospective study was conducted at a referral center in Rio de Janeiro, Brazil. Patients presenting with metastatic or non-metastatic LRGTN (risk score ≤ 6) in non-probabilistic sampling were assigned to 1 of 3 treatments: methotrexate with folinic acid rescue (MTX-CF; n=20); actinomycin D (n=20); and etoposide (n=20). Women with less than 1 year of disease-free follow-up after the first normal human chorionic gonadotropin (hCG) value were excluded. Outcome measures included primary remission rate; resistance to primary and sequential chemotherapy; period between treatment initiation and remission (hCG response); and prevalence of toxic effects.
RESULTS: Primary remission was achieved by 48 patients (80.0%). The remission rate with etoposide was 100.0%, while the rates with actinomycin D and MTX-CF were 90.0% and 50.0%, respectively. Efficacy of etoposide was significantly greater than the other 2 agents (P<0.001). Alopecia was the most frequent adverse effect caused by etoposide. Common to all protocols were stomatitis, nausea, and vomiting. Mean time intervals between beginning treatment and remission were similar and all 60 participants survived.
CONCLUSION: Etoposide was the most effective regimen for treating metastatic and non-metastatic LRGTN.

Lurain JR, Chapman-Davis E, Hoekstra AV, Schink JC
Actinomycin D for methotrexate-failed low-risk gestational trophoblastic neoplasia.
J Reprod Med. 2012 Jul-Aug; 57(7-8):283-7 [PubMed] Related Publications
OBJECTIVE: To determine outcomes and factors associated with failure of 5-day actinomycin D for treatment of methotrexate-failed low-risk gestational trophoblastic neoplasia (GTN).
STUDY DESIGN: We reviewed the records of 358 patients treated with methotrexate 0.4 mg/kg (max 25 mg) IV push q.d. x 5 d every 14 d for FIGO-defined, low-risk GTN between 1979 and 2009. Actinomycin D 0.5 mg IV push q.d. x 5 d every 14 d was given to 64 of 68 patients (18%) who failed methotrexate: 48 (75%) for resistance and 16 (25%) for toxicity. Adjuvant surgery was used in selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively.
RESULTS: The complete response rate to secondary chemotherapy with actinomycin D for failed methotrexate treatment of low-risk GTN was 75% (48/64), including 71% (34/48) for methotrexate resistance and 88% (14/16) for methotrexate toxicity. All 20 patients (6%) who failed sequential single-agent chemotherapy with methotrexate and actinomycin D were placed into permanent remission with the use of multiagent chemotherapy with or without surgery. The only factor significantly associated with resistance to secondary actinomycin D chemotherapy was clinicopathologic diagnosis of choriocarcinoma versus postmolar GTN (56% versus 20%, p = 0.025).
CONCLUSION: Actinomycin D 0.5 mg IV q.d. x 5 d every 14 d used as secondary therapy in methotrexate-failed low-risk GTN resulted in a 75% complete response rate and eventual 100% cure with subsequent multiagent chemotherapy with or without surgery. Resistance to sequential methotrexate and actinomycin D chemotherapy was significantly associated with original FIGO score > or = 3 and clinicopathologic diagnosis of choriocarcinoma.

Alazzam M, Tidy J, Hancock BW, et al.
First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2012; (7):CD007102 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear.
OBJECTIVES: To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN.
SEARCH METHODS: In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review.
SELECTION CRITERIA: For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials.
MAIN RESULTS: We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women).Overall, dactinomycin was associated with significantly higher rates of primary cure than methotrexate (five studies, 513 women; RR 0.64, 95% Confidence Interval (CI) 0.54 to 0.76). Methotrexate was associated with significantly more treatment failure than dactinomycin (five studies, 513 women; RR 3.81, 95% CI 1.64 to 8.86). We consider this evidence to be of a moderate quality.There was no significant difference between the two groups with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too heterogeneous to be conclusive. No severe adverse effects (SAEs) occurred in either group in three out of the five included studies and there was no significant difference in SAEs between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%), however, there was a trend towards fewer SAEs in the methotrexate group. We considered this evidence to be of a low quality due to substantial heterogeneity and low consistency in the occurrence/reporting of SAEs between trials.
AUTHORS' CONCLUSIONS: Dactinomycin is more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, compared with methotrexate. There is limited evidence relating to side-effects, however, the pulsed dactinomycin regimen does not appear to be associated with significantly more side-effects than the low-dose methotrexate regimen and therefore should compare favourably to the five- and eight-day methotrexate regimens in this regard.We consider pulsed dactinomycin to have a better cure rate than, and a side-effect profile at least equivalent to, methotrexate when used for first-line treatment of low-risk GTN. Data from a large ongoing trial of pulsed dactinomycin compared with five- and eight-day methotrexate regimens is likely to have an important impact on our confidence in these findings.

Merkel O, Wacht N, Sifft E, et al.
Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia.
Leukemia. 2012; 26(12):2508-16 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

Edwards AY, Skolnik JM, Dombrowsky E, et al.
Modeling and simulation approaches to evaluate pharmacokinetic sampling contamination from central venous catheters in pediatric pharmacokinetic studies of actinomycin-D: a report from the children's oncology group.
Cancer Chemother Pharmacol. 2012; 70(1):83-94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The binding of drugs to catheters can be a source variation in dosing chemotherapeutics. Drug contamination from the dosing central venous line (CVL) can impact the reporting of pharmacokinetic (PK) results and analysis. Peripheral venipuncture avoids binding complications from the CVL but dissuades patients from enrolling. Our group has developed a catheter clearing procedure to minimize the extent of contamination so that dosing and sampling from the CVL can ensue, promoting patient willingness to participate in phase I pediatric oncology trials.
OBJECTIVES: To develop a population pharmacokinetic model of actinomycin-D (AMD) in children with cancer incorporating expressions for drug contamination from PK samples obtained via indwelling CVLs and to evaluate the efficiency of a catheter clearing procedure in removing contamination as well as the impact of contamination on PK results.
METHODS: A dataset of 199 AMD plasma concentration measurements from 36 patients (age 1.6-20.3 years) was analyzed using nonlinear mixed-effects modeling. Quantitative modeling approaches, including baseline contamination model, covariate model, and catheter clearance model, were evaluated to describe catheter contamination. Monte Carlo simulations mimicking a prospective study in children with cancer were performed to assess the performance of the final model and impact of catheter contamination on PK reporting.
RESULTS: The PK of AMD was best described by a linear 3-compartment model with first-order elimination. A baseline contamination model including a contamination factor proportional to the model-predicted concentration for samples obtained from central catheters was chosen as the most parsimonious and accurate among competing models. The final model parameters were allometrically scaled to a 70 kg person. The estimated mean parameter values were 11 L/h, 5.79, 24.2, 490 L, 17.7, and 42.8 L/h for total clearance, central volume of distribution, peripheral volume 1, peripheral volume 2, inter-compartmental clearance 1, and inter-compartmental clearance 2, respectively. The proportional contamination factor was 19.3 % immediately post-drug administration and decreased at a first-order rate of 0.0932 h(-1). Simulations precisely re-estimated kinetic parameters with catheter contamination adjustment. Large uncertainty and poor estimation were observed when contamination was ignored.
CONCLUSIONS: Drug contamination from sampling catheter can impact AMD PK results and should be accounted for in the analysis. We provide a framework for evaluating catheter contamination and guidance on adjustment in the PK model.

Guo L, Fan L, Ren J, et al.
Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer.
Int J Nanomedicine. 2012; 7:1449-60 [PubMed] Free Access to Full Article Related Publications
The intractability of non-small cell lung cancer (NSCLC) to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD) can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4) or 5 (DR5). However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which TRAIL liposomes are safely combined with ActD liposomes.

Chitsike I, Masanganise R, Sibanda D, Kuona P
Rhabdomyosarcoma of the orbit in a four months old infant in Zimbabwe: A case report.
Cent Afr J Med. 2012 May-Aug; 58(5-6):26-9 [PubMed] Related Publications
Infants younger than one year of age with Rhabdomyosarcoma appear to have worse prognosis compared to older children due partly to high rates of local failure. We report a 4 months old infant with orbital rhabdomyosarcoma with poor outcome. Reluctance to use aggressive local control measures and suboptimal chemotherapy dosing are significant contributory factors. Call is made for need for more studies to determine appropriate local therapy in infants with rhabdomyosarcoma.

Chapman-Davis E, Hoekstra AV, Rademaker AW, et al.
Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy.
Gynecol Oncol. 2012; 125(3):572-5 [PubMed] Related Publications
OBJECTIVE: To determine factors associated with resistance to methotrexate treatment of low-risk gestational trophoblastic neoplasia (GTN).
METHODS: We reviewed the records of 358 patients with low-risk GTN (FIGO stage I and stages II-III, score<7) treated initially with methotrexate 0.4 mg/kg (max 25mg) IV push daily × 5 days every 14 days between 1979 and 2009. Actinomycin D 0.5mg IV push daily × 5 days every 14 days was used in 64 patients who developed resistance or toxicity to initial methotrexate chemotherapy, and combination drug regimens were used in 20 patients who failed single-agent chemotherapy. Adjuvant surgery was used in 34 selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively.
RESULTS: The complete response rate to initial methotrexate chemotherapy was 81% (290/358) and the complete response rate to actinomycin D as secondary therapy was 75% (48/64), for an overall complete response rate to sequential single-agent chemotherapy of 94% (338/358). The remaining 20 patients (6%) were all placed into permanent remission with the use of multiagent chemotherapy with or without surgery. Resistance to initial methotrexate chemotherapy was associated with increasing FIGO score (p<.0001), clinicopathologic diagnosis of choriocarcinoma (p=.028), higher pretreatment hCG (p=0.001) and presence of metastatic, disease (p=.018).
CONCLUSIONS: Sequential single-agent chemotherapy with methotrexate (0.4 mg/kg-max 25mg) followed by actinomycin D (0.5mg) each given IV push for 5 consecutive days every other week for treatment of low-risk GTN resulted in only 6% of patients requiring multiagent chemotherapy and a 100% survival rate.

Chai CY, Deneve JL, Beasley GM, et al.
A multi-institutional experience of repeat regional chemotherapy for recurrent melanoma of extremities.
Ann Surg Oncol. 2012; 19(5):1637-43 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hyperthermic isolated limb perfusion (HILP) or isolated limb infusion (ILI) are well-accepted regional chemotherapy techniques for in-transit melanoma of extremity. The role and efficacy of repeat regional chemotherapy for recurrence and which salvage procedure is better remains debatable. We aimed to compare toxicities and clinical outcomes by procedure types and the sequence.
METHODS: Data from 44 patients, who underwent repeat HILPs or ILIs from 3 institutions beginning 1997 to 2010, were retrospectively reviewed. Regional toxicity assessed by Wieberdink grade, systemic toxicity assessed by serum creatine phosphokinase level, length of hospital stay (LOS), response rates at 3 months after the procedure, and time to in-field progression (TTP) were analyzed.
RESULTS: Of 44 patients, 46% were men and 54% women with a median age of 66 (range 29-85) years at diagnosis. The median follow-up was 21.4 (range 4-153) months. Of 70 ILIs and 28 HILPs, the following groups were identified: group A, ILI → ILI (n = 25); group B, ILI → HILP (n = 10); group C, HILP → ILI (n = 12); and group D, HILP → HILP (n = 3). The comparison of Wieberdink grade, serum creatine phosphokinase level, LOS, and response rate between procedures (HILP vs. ILI), between sequence (initial vs. repeat), and among their interactions showed no statistically significant differences. TTP after initial procedure did not differ between HILP and ILI (P = 0.08), and no survival difference was seen (P = 0.65) when TTP after repeat procedure was compared.
CONCLUSIONS: Most patients tolerated repeat regional chemotherapy without increased toxicity or LOS. No statistical difference in clinical outcomes was noted when comparing repeat procedures, even though repeat HILPs showed higher complete response compared to repeat ILIs.

Mousavi A, Cheraghi F, Yarandi F, et al.
Comparison of pulsed actinomycin D versus 5-day methotrexate for the treatment of low-risk gestational trophoblastic disease.
Int J Gynaecol Obstet. 2012; 116(1):39-42 [PubMed] Related Publications
OBJECTIVE: To determine the effectiveness of 2 standard chemotherapy regimens for low-risk gestational trophoblastic disease according to the International Federation of Gynecology and Obstetrics (FIGO) staging system.
METHODS: From 2008 until 2010, 75 women with low-risk gestational trophoblastic disease received either pulsed actinomycin D (n=50) or 5-day methotrexate (n=25). The primary remission rate, the duration of treatment, the number of treatment courses, and the adverse effects were compared.
RESULTS: The complete remission rates were 90% for the actinomycin D group and 68% for the methotrexate group (P=0.018). The mean number of chemotherapy courses administered to achieve complete remission (including courses of second-line therapy) was 3.1 in the methotrexate group and 5.3 in the actinomycin D group (P=0.01). No major adverse effects were experienced in either treatment group and there were no significant differences in terms of adverse effects. Second-line chemotherapy was indicated for 11 patients.
CONCLUSION: Based on the present study, pulsed actinomycin D seems to be an appropriate first-line treatment for patients with low-risk gestational trophoblastic disease.

Chun JY, Hussain M, Powell B, Belli AM
Technique and outcomes of isolated limb infusion for locally advanced malignant melanoma--a radiological perspective.
Clin Radiol. 2011; 66(12):1175-80 [PubMed] Related Publications
AIM: Isolated limb infusion (ILI) is a novel, minimally invasive technique for delivering high-dose regional chemotherapy in patients with recurrent and in-transit melanoma. The aim of this study was to review our single-centre experience in treating eleven patients. We emphasize the role of radiologists in setting up this service, including pre-treatment workup and placement of vascular catheters.
MATERIALS AND METHODS: A retrospective analysis of 11 patients who underwent 12 procedures between 2005 and 2009 was performed. Pre-procedural staging computed tomography (CT), CT angiography, and duplex studies were performed. All patients received a cytotoxic combination of melphalan and actinomycin-D via radiologically placed arterial and venous catheters in the affected limb under mild hyperthermic conditions. The outcome measures include response rates, limb toxicity, complications, and survival.
RESULTS: All patients were female with a mean age of 72 years. Three patients had American Joint Committee on Cancer (AJCC) stage IIIB melanoma, seven had stage IIIC melanoma, and one had a stage IIIB Merkel cell tumour. Complete response was seen in five patients (46%), partial response in four (36%), and progressive disease in two (18%). One patient developed grade 4 toxicity requiring a fasciotomy and another experienced systemic toxicity.
CONCLUSION: These outcomes are comparable to previous studies and shows that ILI is effective in locoregional control of unresectable melanoma. It is a relatively safe procedure but not without risk. Our experience shows the importance of radiological input to ensure safe and effective delivery of services.

Rao B, van Leeuwen IM, Higgins M, et al.
Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy.
Oncotarget. 2010; 1(7):639-50 [PubMed] Free Access to Full Article Related Publications
p53-Based cyclotherapy is proving to be a promising approach to palliate undesired effects of chemotherapy in patients with tumours carrying p53 mutations. For example, pre-treatment of cell cultures with Nutlin-3, a highly-selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not p53-defective cells, from subsequent treatment with mitotic poisons or S-phase specific drugs. Here we sought to evaluate whether low doses of Actinomycin D (LDActD), a clinically-approved drug and potent p53 activator, could substitute Nutlin-3 in p53-based cyclotherapy. We found that pre-treatment with LDActD before adding the aurora kinase inhibitor VX-680 protects normal fibroblasts from polyploidy and nuclear morphology abnormalities induced by VX-680. However, and although to a lower extent than normal fibroblasts, tumour cell lines bearing p53 mutations were also protected by LDActD (but not Nutlin-3) from VX-680-induced polyploidy. We also report that a difference between the response of p53 wild-type cells and p53-defective cells to the LDActD/VX-680 sequential combination is that only the former fail to enter S-phase and therefore accumulate in G1/G0. We propose that drugs that incorporate into DNA during S-phase may perform better as second drugs than mitotic poisons in cyclotherapy approaches using LDActD as a cytostatic agent.

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