Cancer Chemotherapy and Pharmacology

Our medical research library holds 26 studies published in Cancer Chemotherapy and Pharmacology (1997–2023). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 26 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Springer Verlag
• Published: 1978 to the present, Germany
• Language: English
• ISSN: 0344-5704 (print), 1432-0843 (electronic)
• Its record in the NLM Catalog

2020s

• Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial. N. de Rouw, R.J. Boosman, J.A. Burgers, et al. 2023;91(1):33-42. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Purpose: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.

  Methods: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.

  Results: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).

  Conclusion: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.

  Clinical Trial Number: Clinicaltrials.gov identifier: NCT03655821.

  © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

• Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma. Z. Ahmad, B.A. Jacobson, M.W. McDonald, et al. 2020;85(2):425-432. PubMed · Publisher

  Abstract

  Activated cap-dependent translation promotes cancer by stimulating translation of mRNAs encoding malignancy-promoting proteins. The nucleoside monophosphate Protide, 4Ei-10, undergoes intracellular uptake and conversion by Hint1 to form 7-Cl-Ph-Ethyl-GMP. 7-Cl-Ph-Ethyl-GMP is an analog of cap and inhibits protein translation by binding and sequestering eIF4E thus blocking eIF4E from binding to the mRNA cap. The effects of inhibiting translation initiation by disruption of the eIF4F complex with 4Ei-10 were examined in malignant mesothelioma (MM). In a cell-free assay system, formation of the eIF4F complex was disabled in response to exposure to 4Ei-10. Treatment of MM with 4Ei-10 resulted in decreased cell proliferation, increased sensitivity to pemetrexed and altered expression of malignancy-related proteins. In light of these findings, suppression of translation initiation by small molecule inhibitors like 4Ei-10 alone or in combination with pemetrexed represents an encouraging strategy meriting further evaluation in the treatment of MM.

2010s

• The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment. V. Galani, A. Varouktsi, S.S. Papadatos, et al. 2019;84(2):241-253. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

• The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer. L.H. Matherly, Z. Hou, A. Gangjee. 2018;81(1):1-15. Review PubMed · Publisher · Free full text

  Abstract

  This review considers the "promise" of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting.

• Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors. S. Aspeslagh, K. Shailubhai, R. Bahleda, et al. 2017;79(6):1257-1265. PubMed · Publisher

  Abstract

  Background: This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors.

  Design: Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m2/day, n = 3; 60 mg/m2/day, n = 3; and 80 mg/m2/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m2/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle.

  Results: All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m2/day and gemcitabine 1000 mg/m2/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6-14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine.

  Conclusion: The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m2/day for milciclib and 1000 mg/m2/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.

• Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition. G. Srinivasan, G.S. Sidhu, E.A. Williamson, et al. 2017;80(4):861-867. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.

• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors. T. Shimizu, K. Fukuoka, M. Takeda, et al. 2016;77(5):997-1003. PubMed · Publisher · Free full text

  Abstract

  Purpose: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.

  Methods: VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.

  Results: Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).

  Conclusions: VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

• Effect of renal function on pemetrexed-induced haematotoxicity. Y. Ando, T. Hayashi, M. Ujita, et al. 2016;78(1):183-9. PubMed · Publisher · Free full text

  Abstract

  Purpose: Pemetrexed (PEM) is an anticancer agent used for the treatment of non-small cell lung cancer, malignant pleural mesothelioma and thymoma. Reportedly, PEM has higher efficacy and safety when used in combination with platinum-based agents. However, there are only few reports on the safety of PEM in patients with an eGFR of ≤45 mL/min. We examined the effect of renal function on the safety of regimens containing PEM.

  Methods: We retrospectively reviewed 221 patients with lung cancer, malignant pleural mesothelioma or thymoma who received treatment with a PEM-containing regimen between 2009 and 2014. Subgroup analyses were performed on the basis of pre-treatment renal function: group A [creatinine clearance (CLcr), <45 mL/min]; group B (CLcr, 45-80 mL/min); and group C (CLcr, ≥80 mL/min). For the purpose of this analysis, the lowest documented blood cell counts and haemoglobin levels, the highest levels of serum creatinine, aspartate aminotransferase, alanine aminotransferase and CLcr from the time of initial administration up to prior to the start of second administration were considered.

  Results: Groups A, B and C had 8, 123 and 90 patients, respectively. The incidence of grade 2 thrombocytopaenia was significantly higher in group A as compared to that in groups B (P < 0.01) and C (P < 0.05). On multivariate analysis, only a CLcr of <45 mL/min was an independent risk factor for thrombocytopaenia of ≥grade 2.

  Conclusion: When administering a PEM-containing regimen, thrombocytopaenia of ≥grade 2 is more likely to develop in patients with a CLcr of <45 mL/min.

• Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection. A. Gupta, Z. Hussein, R. Hassan, et al. 2016;77(4):733-43. PubMed · Publisher · Free full text

  Abstract

  Purpose: To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.

  Methods: A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.

  Results: Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship.

  Conclusions: In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma. O. Arrieta, D. López-Macías, V.O. Mendoza-García, et al. 2014;73(5):975-82. PubMed · Publisher

  Abstract

  Purpose: Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged infusion plus cisplatin in patients with advanced pleural mesothelioma.

  Methods: Patients with mesothelioma received gemcitabine (250 mg/m(2)) in a 6-h infusion plus cisplatin (35 mg/m(2)) on days 1 and 8 every three weeks. We used the modified response evaluation criteria in solid tumours. This study is registered in clinical trials (NCT01869023).

  Results: We included 39 patients; 82.1 % were low risk according to the European Organisation for Research and Treatment of Cancer prognostic group. Partial response was observed in 53.8 % (21/39), stable disease in 33.3 % (13/39) and progression in 12.8 % (5/39). The median progression-free survival was 6.9 months (95 % CI 3.2-10.6 months), and the associated factors were the EORTC risk and histology. The median overall survival was 20.7 months (95 % CI 10.7-30.8 months). The functional, physical and emotional roles and dyspnoea, insomnia and pain symptom scales improved. The most commonly graded 3/4 side effects were neutropenia (24.4 %), lymphopenia (14.6 %), thrombocytopenia (14.7 %) and anaemia (12.2 %).

  Conclusions: Low-dose, prolonged gemcitabine infusion plus cisplatin has acceptable toxicity and high efficacy with improved quality of life, representing an affordable regimen for the low-income population.

• High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with (99m)Tc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin. O. Arrieta, L.A. Medina, E. Estrada-Lobato, et al. 2014;74(1):211-5. PubMed · Publisher

  Abstract

  Background: There are currently no available biomarkers for advanced pleural mesothelioma that determine which patients could benefit from a specific chemotherapy regimen.

  Methods: Based on the results of a previously published phase II study, we associated the (99m)Technetium-labelled liposomal doxorubicin ((99m)Tc-LD) uptake value (75 % cut-off) with the response rate, progression-free survival and overall survival of patients treated with a combination of liposomal doxorubicin and cisplatin.

  Results: Patients with tumours exhibiting increased (99m)Tc-LD uptake showed better response rates, progression-free survival and overall survival than those exhibiting lower uptake 73.3 versus 15 % (p < 0.001); 6.9 versus 3.2 months (p = 0.033) and 23 versus 6.6 months (p = 0.001), respectively.

  Conclusion: (99m)Tc-DL uptake in tumour tissue could define a set of patients who would benefit from this chemotherapy regimen.

• Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts. P.M. Tedeschi, Y.K. Kathari, I.N. Farooqi, et al. 2014;74(5):1029-32. PubMed · Publisher · Free full text

  Abstract

  Purpose: To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.

  Methods: H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.

  Results: In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.

  Conclusions: High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.

• Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients. P.H. Honoré, S.J. Joensen, M. Olsen, et al. 2014;74(2):349-57. PubMed · Publisher

  Abstract

  Aim: Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly.

  Method: Eight patients treated with a 500 mg/m(2) PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model.

  Results: The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V(central)) 23.2 L and peripheral volume distribution (V(peripheral)) 10.6 L, and the area under the curve was 186 μg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h.

  Conclusion: Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.

• Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas. S. Kummar, M.E. Gutierrez, L.W. Anderson, et al. 2013;72(4):917-23. PubMed · Publisher · Free full text

  Abstract

  Purpose: Batracylin (daniquidone), an ATP-insensitive topoisomerase I/II inhibitor, demonstrated wide interspecies variation in preclinical models consistent with formation of a toxic metabolite, N-acetyl-batracylin, following metabolism by N-acetyl-transferase 2 (NAT2). To minimize exposure to this toxic metabolite, this first-in-human study was conducted in patients with advanced refractory solid tumors or lymphomas demonstrated to have a slow NAT2 acetylator genotype. The objectives were to determine the safety, maximum tolerated dose (MTD), and pharmacokinetics of batracylin and its metabolites.

  Methods: Based on the MTD for rats, the most sensitive species, the starting dose was 5 mg/day for 7 days in 28-day cycles. Dose escalation followed accelerated titration design 4B, with restaging performed every 2 cycles.

  Results: Thirty-one patients were enrolled. Treatment was well tolerated; one patient experienced grade 3 toxicity (lymphopenia). Dose escalation was stopped at 400 mg/day due to grade 1 and 2 hemorrhagic cystitis. No objective responses were observed, but prolonged disease stabilization was observed in 2 patients, one with peritoneal mesothelioma (8 cycles) and another with adrenocortical cancer (18 cycles). Across an 80-fold range of doses, the ratios of systemic exposures for batracylin and N-acetyl batracylin were near 1.

  Conclusions: Pharmacogenetically selected patients reached a dose that was 20-fold higher than the MTD in rats and 70 % of the MTD in mice. This genotype-guided strategy was successful in safely delivering batracylin to patients. However, due to unexpected cystitis, not preventable by hydration, and in the absence of a stronger signal for antitumor activity, further development of batracylin has been stopped.

• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma. D.R. Camidge, N. Blais, D.J. Jonker, et al. 2013;71(2):307-19. PubMed · Publisher

  Abstract

  Purpose: To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

  Methods: Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles.

  Results: Sunitinib 37.5 mg/pemetrexed 400 mg/m(2)/cisplatin 75 mg/m(2) CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m(2)/cisplatin 75 mg/m(2), based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug-drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥ 8 weeks, and the one patient with mesothelioma had a partial response.

  Conclusions: In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.

• Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter. C. Cherian, S. Kugel Desmoulin, L. Wang, et al. 2013;71(4):999-1011. PubMed · Publisher · Free full text

  Abstract

  Purpose: We examined whether the novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate, compound 2, might be an effective treatment for malignant pleural mesothelioma (MPM), reflecting its selective membrane transport by the proton-coupled folate transport (PCFT) over the reduced folate carrier (RFC).

  Methods: HeLa sublines expressing exclusively PCFT (R1-11-PCFT4) or RFC (R1-11-RFC6) and H2452 MPM cells were assayed for transport with [(3)H]compound 2. [(3)H]Polyglutamate metabolites of compound 2 were measured in R1-11-PCFT4 and H2452 cells. In vitro cell proliferation assays and colony formation assays were performed. Inhibition of glycinamide ribonucleotide formyltransferase (GARFTase) was assayed by nucleoside protection assays and in situ GARFTase assays with [(14)C]glycine. In vivo efficacy was established with early- and advanced-stage H2452 xenografts in severe-combined immunodeficient (SCID) mice administered intravenous compound 2.

  Results: [(3)H]Compound 2 was selectively transported by PCFT and was metabolized to polyglutamates. Compound 2 selectively inhibited proliferation of R1-11-PCFT4 cells over R1-11-RFC6 cells. H2452 human MPM cells were sensitive to the antiproliferative effects of compound 2. By colony-forming assays with H2452 cells, compound 2 was cytotoxic. Compound 2 inhibited GARFTase in de novo purine biosynthesis. In vivo efficacy was confirmed toward early- and advanced-stage H2452 xenografts in SCID mice administered compound 2.

  Conclusions: Our results demonstrate potent antitumor efficacy of compound 2 toward H2452 MPM cells in vitro and in vivo, reflecting its efficient membrane transport by PCFT, synthesis of polyglutamates, and inhibition of GARFTase. Selectivity for non-RFC cellular uptake processes by tumor-targeted antifolates such as compound 2 presents an exciting new opportunity for treating solid tumors.

• A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma. Z.G. Zimling, J.B. Sørensen, T.A. Gerds, et al. 2012;70(5):743-54. PubMed · Publisher

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III β-tubulin in a cohort of MPM patients treated with cisplatin-vinorelbine. We further explored the possibility of combining markers into a treatment-response profile to increase the predictive power.

  Methods: Formalin-fixed paraffin-embedded tumor specimens from 54 MPM patients included in a phase II trial were evaluated for ERCC1, BRCA1, and class III β-tubulin by immunohistochemistry (IHC). Immunostaining was quantified by an H-score and dichotomized according to upper quartile values. The ERCC1- and class III β-tubulin-status classified patients as treatment resistant (ERCC1 positive + class III β-tubulin positive) or treatment responsive (ERCC1 negative + class III β-tubulin negative). The remaining marker combinations were considered inconclusive.

  Results: Fifty patients had tumor tissue available for IHC. Eleven had a responsive profile, and nine had a resistant profile. Thirty patients had an inconclusive profile. Median progression-free survival (PFS) was 6.7 months in the treatment-resistant group, 15.3 months in the treatment-responsive group, and 8.1 months in the inconclusive group (log-rank p = 0.03). Multivariate analysis revealed that treatment-resistant patients had a decreased PFS and overall survival (OS) compared with the treatment-responsive patients (HR 6.45, CI 95 % [2.02-20.64] p = 0.002 and HR 4.64, CI 95 % [1.56-13.79], p = 0.006, respectively). BRCA1 status was associated with neither PFS nor OS.

  Conclusion: Combined negative ERCC1 and class III β-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.

• In vitro anti-mesothelioma activity of cisplatin-gemcitabine combinations: evidence for sequence-dependent effects. I. Zanellato, C.D. Boidi, G. Lingua, et al. 2011;67(2):265-73. PubMed · Publisher

  Abstract

  Purpose: The present study addresses the optimization of gemcitabine-cisplatin protocols currently adopted in the clinical management of malignant pleural mesothelioma (MPM), using cell lines derived from different histological subtypes of MPM as an in vitro model.

  Methods: MPM cell lines were exposed either to single drugs or to their combinations, using a fixed dose ratio. Possible mechanisms for synergistic interactions were investigated by cell cycle analysis, western blot analysis of p53 phosphorylation status, and neutral comet assay to detect double strand breaks.

  Results: Four-hour pre-treatment with gemcitabine followed by 68-h exposure to cisplatin was found to exert synergistic activity in both epithelioid and sarcomatoid MPM subtypes, inducing a strong S-phase arrest that correlated with accumulation of double-strand breaks (DSBs).

  Conclusion: The antiproliferative effects of the gemcitabine/cisplatin combination in mesothelioma cells can be maximized by pre-treatment with gemcitabine, suggesting that this drug increases cisplatin-induced DSBs by inhibiting DNA adduct repair.

• Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients. T. Takahashi, Y. Nakamura, A. Tsuya, et al. 2011;68(3):653-9. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Purpose: This study was conducted to determine the pharmacokinetics of aprepitant and dexamethasone as well as the relationship between the plasma concentration of substance P and nausea/vomiting in Japanese cancer patients.

  Methods: After administration of aprepitant (125/80 mg group [10 patients]: 125 mg on day 1 and 80 mg on days 2-5; 40/25 mg group [10 patients]: 40 mg on day 1 and 25 mg on days 2-5) and dexamethasone (6 mg on day 1 and 4 mg on days 2 and 3 in the 125/80 mg group, and 8 mg on day 1 and 6 mg on days 2 and 3 in the 40/25 mg group) to Japanese cancer patients receiving at least moderately emetogenic antitumor agents, the plasma concentrations of aprepitant, dexamethasone, and substance P were measured.

  Results: All of 20 patients were treated with the highly emetogenic agent cisplatin (≥70 mg/m(2)). The C(max) and AUC(0-24 h) of aprepitant in Japanese cancer patients were similar with those in non-Japanese patients. The clearance of dexamethasone in the 125/80 mg group was approximately one-half of that previously determined in the absence of aprepitant. The substance P concentration in plasma significantly increased only in patients with delayed nausea/vomiting.

  Conclusions: This study demonstrated similar plasma pharmacokinetics of aprepitant in Japanese and non-Japanese, the validity of reducing dexamethasone dose, and the existence of increased plasma substance P concentration in patients receiving highly emetogenic cisplatin-based chemotherapy.

• Review on clinical trials of targeted treatments in malignant mesothelioma. J.N. Jakobsen, J.B. Sørensen. 2011;68(1):1-15. Review PubMed · Publisher

  Abstract

  Purpose: Malignant mesothelioma (MM) is an aggressive tumor of the serosal surfaces with a poor prognosis. Advances in the understanding of tumor biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. This article is a comprehensive review of all clinical trials evaluating the effect of targeted treatments in MM.

  Methods: An extensive literature search was performed in January 2011 using pubmed and medline. No constraints on publication date were applied.

  Results: Thirty-two trials exploring 17 different targeted agents in MM were found. Treatment in first- and second-line targeted agents induced response rates ranging from 0-14% and 0-16%, respectively. The tyrosine kinase inhibitor sunitinib induced partial response in 10% and stable disease in 66% of MPM patients as second-line treatment. A preliminary analysis of a phase II/III trial suggests that addition of bevacizumab to pemetrexed and cisplatin first-line treatment significantly improves disease control (CR + PR + SD) in the bevacizumab arm (73.5%) compared with treatment with pemetrexed and cisplatin without bevacizumab (43.2%) (P = 0.010). Another phase II trial did not observe any significant clinical benefit of adding of bevacizumab to gemcitabine and cisplatin.

  Conclusions: Disease stabilization is reported in some patients with several targeted treatments and might be beneficial in subgroups of patients or in combination with classic chemotherapy. None of the hitherto explored targeted treatments can currently be recommended as standard treatment in MM.

• The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice. T.T. Van, M. Hanibuchi, S. Kakiuchi, et al. 2011;68(2):497-504. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM.

  Methods: We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle.

  Results: The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice.

  Conclusions: We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.

• Resistance to platinum-based chemotherapy in lung cancer cell lines. J. Chen, N. Emara, C. Solomides, et al. 2010;66(6):1103-11. PubMed · Publisher · Free full text

  Abstract

  Purpose: A series of six lung cancer cell lines of different cell origin (including small cell and mesothelioma) were characterized immunohistochemically and the role of a series of protein candidates previously implicated in drug resistance were investigated.

  Methods: These include colony-forming and cell growth assays, immunohistochemistry, siRNA knockouts, real-time PCR and western blots.

  Results: No correlation was found with AKT, HO-1, HO-2, GRP78, 14-3-3zeta and ERCC1 levels and cisplatin nor oxaliplatin cytotoxicity, but an association was observed with levels of the enzyme, dihydrodiol dehydrogenase (DDH); an enzyme previously implicated in the development of platinum resistance. The relationship appeared to hold true for those cell lines derived from lung epithelial primary tumors but not for the neuroendocrine/small-cell and mesothelioma cell lines. siRNA knockouts to DDH-1 and DDH-2 were prepared with the cell line exhibiting the greatest resistance to cisplatin (A549) resulting in marked decreases in the DDH isoforms as assessed by real-time PCR, western blot and enzymatic activity. The DDH-1 knockout was far more sensitive to cisplatin than the DDH-2 knockout.

  Conclusion: Thus, sensitivity to cisplatin appeared to be associated with DDH levels in epithelial lung cancer cell lines with the DDH-1 isoform producing the greatest effect. Results in keeping with transfection experiments with ovarian and other cell lines.

• Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines. Y. Wang, A.K. Rishi, V.T. Puliyappadamba, et al. 2010;66(3):455-66. PubMed · Publisher · Free full text

  Abstract

  Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies.

  Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent.

  Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines.

  Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins.

  Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.

• The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors. B.S. Choi, D.B. Alberti, W.R. Schelman, et al. 2010;66(5):973-80. PubMed · Publisher · Free full text

  Abstract

  Purpose: 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.

  Methods: 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.

  Results: 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.

  Conclusions: 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.

2000s

• Expression and integrity of DNA topoisomerase II isoforms does not explain generic drug resistance in malignant mesothelioma. B.R. McLaren, D. Whitaker, B.W. Robinson, et al. 2001;48(1):1-8. PubMed · Publisher

  Abstract

  Purpose: Malignant mesothelioma is a tumour that is highly resistant to a number of different chemotherapy agents, yet the mechanisms by which resistance occurs are poorly understood. The pattern of resistance is consistent with disruption of topoisomerase function or expression. Coupled with this, we have previously noted a common serological reaction to the beta isoform of topoisomerase II, suggesting that it may be aberrantly expressed in patients with mesothelioma.

  Methods: We assessed the expression of topoisomerase II isoforms in sections of primary tumour. We tested a panel of five mesothelioma cell lines for sensitivity to the known topoisomerase-targeting drugs, doxorubicin and etoposide. We sequenced expressed segments of the topoisomerase genes from these cell lines that have previously been associated with drug resistance. We then investigated other potential resistance mechanisms.

  Results: We found that the beta isoform of topoisomerase II was more frequently expressed in primary tumours. Only one of the five cell lines was highly resistant to etoposide and this cell line was found to have a point mutation in the gene for topoisomerase IIalpha. Protein levels of topoisomerase IIalpha and beta did not correlate with sensitivity to either doxorubicin nor to etoposide. Semiquantitative analysis suggested that there was marked variation in the levels of mRNA expression of MRP, gamma-GCS and MDR1. None of these findings could be associated with resistance to chemotherapy.

  Conclusion: We conclude that mutations in topoisomerase IIalpha can be associated with extreme resistance of mesothelioma to etoposide. The generic drug resistance of this tumour requires further investigation.

1990s

• Potentiation of cisplatin and carboplatin cytotoxicity by amphotericin B in different human ovarian carcinoma and malignant peritoneal mesothelioma cells. L. Poulain, F. Sichel, H. Crouet, et al. 1997;40(5):385-90. PubMed · Publisher

  Abstract

  An in vitro study of the combined cytotoxicity of either cisplatin (CDDP) or carboplatin and amphotericin B (AmB) was undertaken on a set of different ovarian carcinoma (IGROVI, IGROVI-C10, OAW42) and peritoneal malignant mesothelioma (CFB-CARP1) cell lines and ascitic cells freshly obtained from ovarian cancer patients so as to investigate the possibility of overcoming their resistance to platinum compounds. Growth-inhibition curves obtained 6 days after a 2-h period of exposure to the drugs showed that AmB at 5-10 mg/l allowed a 5- to 10-fold decrease in the 50% growth-inhibitory concentrations (IC50) of CDDP and carboplatin on either sensitive or resistant cells. Intracellular platinum assays with IGROVI cells showed that AmB acted by increasing dramatically the platinum uptake at a proportion that accounted for the increase in cytotoxicity. In the subline IGROVI-C10, a 10-fold resistant subline of IGROVI, AmB at 10 mg/l allowed recovery to the level of sensitivity seen in the parental cell line in the absence of AmB but not to the level observed in the presence of AmB. Acquisition of resistance mechanisms that are independent of the regulation of platinum uptake might be involved in this cell line. Thus, AmB might act by increasing the intracellular concentration of platinum without modifying the resistance mechanism involved downstream. However, in our models an increase in the intracellular level of platinum was always sufficient for the recovery of chemosensitivity in vitro. We also show that the phosphodiesterase inhibiting methylxanthines act synergistically with AmB. The latter drugs are weakly toxic and could also attenuate the nephrotoxicity of AmB.

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