Clinical Cancer Drugs - Volume 5, Issue 1, 2018

Background: Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors have entered into the clinic rapidly and are becoming a powerful therapeutic tool, especially in the management of BRCA associated ovarian cancers. PARP inhibitors have exploited the homologous recombination deficiency, present in up to 50% of ovarian cancers, through synthetic lethality: A novel therapeutic approach to this disease. Objective: Through an extensive review of PARP inhibitors we evaluated the existing evidence in the clinical trial as monotherapy and combined with chemotherapy in ovarian cancer. Conclusion: PARP inhibitors have demonstrated to fulfill the characteristics of the ideal maintenance therapy agent. Understanding biomarkers in this scenario holds maximum importance to allow its foreseen potential, although “platinum-sensitivity” shows to be a “functional biomarker”, reflecting a homologous recombination deficiency phenotype, thus, proving sensitivity to PARP inhibitors. Many clinical studies are ongoing marking its future directions and analyzing its effect on several combinations. Numerous questions remain unanswered, such as mechanisms of resistance or sequential use, and need to be explored completely through ongoing research.

A tumour which can evolve within the colon and rectum is termed as colorectal cancer. These cancers are named as rectal or colon cancer based on their origin. The colorectal cancers evolve due to polyp formation either on the inner lining of the colon or rectum. Some of the polyps are leading to cancer over the series of several years, but all polyps do not develop cancer. The treatment of colorectal cancer is also possible by surgery, radiation, chemo- and targeted therapy. Oxaliplatin is a platinumbased chemotherapeutic agent, given in a combination with “FOLFOX” (leucovorin and fluorouracil) which is prescribed for the treatment of colorectal cancer. It forms many transient reactive complexes such as monoaquo and Diaquodiaminocyclohexane (DACH) platinum, which are fluently attached with macromolecules. These active platinum complexes are capable of blocking DNA fusion by constituting both cross-linked strand (inter and intra) of DNA molecule. These crosslinks hinder DNA replication and transcription. Both RNA and protein synthesis are inhibited at higher concentration of drug oxaliplatin. The pharmacokinetics of oxaliplatin was assessed on a number of patients by giving the infusion of 2 h with the dose of 85mg/m2. The reported half-lives show large variations between the shortest half-life is 32–47 h and the longest 189–239 h, which are being obtained by Flameless Atomic Absorption Spectroscopy (FAAS) and ICP-MS (Inductively Couple Plasma Mass Spectrometry). Recently, the oxaliplatin was detected within1-3 h thereafter the end of an infusion of 130 mg/m2 of oxaliplatin using liquid chromatography in combination with ICP-MS.

Background: The migration of tumor cells is critical in spreading cancers through the lymphatic nodes and circulatory systems. Although arachidonic acid (AA) and its soluble metabolites have been shown to induce the migration of breast and colon cancer cells, the mechanism by which it induces such migration has not been fully understood. Objective: The effect of AA on migratory responses of the MDA-MB-231 cell line (a triple-negative breast cancer cell) was examined and compared with MCF-7 (estrogen-receptor positive) breast cancer cells to elucidate the mechanism of AA-induced migration. Methods: Migrations of breast cancer cells were examined with the help of wound-healing assays. AA-induced eicosanoid synthesis was monitored by RP-HPLC. Cellular localizations of lipoxygenase and lipid rafts were assessed by immunoblot and confocal microscopy. Results: AA treatment stimulated the synthesis of leukotriene B4 (LTB4) and HETE-8, but lowered the levels of prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and HETE-5 in MDA-MB-231 cells. Further analysis indicated that AA increased the expression of 5-lipoxygenase (5-LOX) in this cell line and inhibiting its expression by small molecule inhibitors lowered the production of LTB4 and reduced migration. In contrast, MCF-7 cells did not show any appreciable changes in eicosanoid synthesis, 5-LOX expression, or cellular migration. Conclusion: Our results suggest that AA treatment activates the BLT1 receptor (present in membrane microdomains) and stimulates the synthesis of LTB4 production, which is likely to be associated with the migration of MDA-MB-231 cells.

Background: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker. Methods: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. Results: GCC protein expression was analyzed by immunoblotting in both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models. Conclusion: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.

Background: Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations, which generate fusion oncogenic proteins. In 95% of cases, in frame fusion of the RARα gene to the PML gene, gives rise to the PML-RARα chimeric gene in patients with t(15;17)q22;q21. In addition, in 99% of cases, APL cells also express the germ cell-specific Cyclin A1 protein, which has been shown to contribute to APL-like disease in mouse models. Re-localization and degradation of PML-RARα with pharmacologic levels of all-trans retinoic acid (ATRA) may cause serious side effects such as the development of myelodysplastic syndrome, cutaneous T-cell lymphoma and skin cancers. Here, we exploit the expression of cyclin A1 and of the fusion protein and show that combined, sub-pharmacologic doses of ATRA and cyclin-dependent kinase inhibitors are more efficacious than either agent alone at inducing etc at inducing APL cell differentiation. Methods: Cultured NB4 APL cells were used to compare the degree of differentiation by ATRA and olomoucine or roscovitine, two cyclin-dependent kinase inhibitors alone or in combination. Differentiation was monitored with the NBT reaction, quantitation of proliferation and monitoring the levels of CDK4, PML-RARα and C/EBP proteins using immunoblots. Results: ATRA or roscovitine alone are effective at inducing inhibition of proliferation and differentiation at pharmacologic levels whereas olomoucine alone is not. In contrast, the combined use of sub-pharmacologic doses of ATRA with either olomoucine or roscovitine is more effective at inhibiting APL cell proliferation than ATRA, olomoucine or roscovitine alone with implications for the treatment of APL. Conclusion: We demonstrate that in NB4 cells, the combination of ATRA/ olomoucine or ATRA/roscovitine leads to more potent differentiation accompanied by a reduction in CDK4 protein levels, decreased degradation of the fusion protein and up-regulation of the transcription factor C/EBPε.

Background: P-glycoprotein expression in tissues acts on pharmacokinetics and pharmacodynamics of drugs. In this context, the C1236T (rs1128503) variant in ATP binding cassette subfamily B member 1 (ABCB1) gene has been linked to inter-individual responses to many drugs. Objective: Our study evaluated the association between clinical and laboratory markers of breast cancer severity, including the recurrence, and C1236T variant in ABCB1 gene. Method: A total of 138 breast cancer patients were enrolled in our study. The rs1128503 screening was done by allele-specific polymerase chain reaction. The following data were registered: selfdeclared ethnicity, body mass index, diabetes mellitus, systemic hypertension, age at menarche, age at menopause, lactation, use of oral contraceptive, use of hormone replacement therapy, neoadjuvant chemotherapy, hormonal therapy after surgery, smoking, radiotherapy, estrogen and progesterone receptor expression, and breast cancer characteristics (recurrence, histological type, histological grade, nuclear grade, TNM staging and clinical stage). Statistical analysis was performed using the Statistical Package for Social Sciences software version 21.0 through the χ2 test, Fisher's exact test and Kruskal-Wallis test. α=0.05 was adopted. Results: The rs1128503*CC genotype and rs1128502*C allele were associated with breast cancer recurrence with an OR=2.256 (95%CI=1.054 to 4.829) and OR=2.112 (95%CI=1.18 to 3.781), respectively. Also, after the correction by multiple tests, only the association between the rs1128502*C allele and recurrence was kept with a p-value<0.05. Conclusion: Our data showed that the rs1128503 variant in ABCB1 gene can contribute to breast cancer recurrence.