Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents

The incidence of melanoma is rising. The primary initial treatment for melanoma continues to be wide local excision of the primary tumor and affected lymph nodes. Exceptions to wide local excision include cases where surgical excision may be cosmetically disfiguring or associated with increased morbidity and mortality. The role of definitive or adjuvant radiotherapy has largely been relegated to palliative measures because melanoma has been viewed as a prototypical radiotherapy-resistant cancer. However, the emerging clinical and radiobiological data summarized here suggests that many types of effective radiation therapy, such as radiosurgery for melanoma brain metastases, plaque brachytherapy for uveal melanoma, intensity modulated radiotherapy for melanoma of the head and neck, and adjuvant radiotherapy for selected high-risk, node-positive patients can improve outcomes. Similarly, although certain chemotherapeutic agents and biologics have shown limited responses, long-term control for unresectable tumors or disseminated metastatic disease has been rather disappointing. Recently, several powerful new biologics and treatment combinations have yielded new hope for this patient group. The recent identification of several clinically linked melanoma gene mutations involved in mitogen-activated protein kinase (MAPK) pathway such as BRAF, NRAS, and cKIT has breathed new life into the drive to develop more effective therapies. Some of these new therapeutic approaches relate to DNA damage repair inhibitors, cellular immune system activation, and pharmacological cell cycle checkpoint manipulation. Others relate to the investigation of more effective targeting and dosing schedules for underutilized therapeutics, such as radiotherapy. This paper summarizes some of these new findings and attempts to give some context to the renaissance in melanoma therapeutics and the potential role for multimodality regimens, which include certain types of radiotherapy as aids to locoregional control in sensitive tissues

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model.

5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization

Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines

Adult T-cell leukemia (ATL), a CD4(+)-T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1), is difficult to cure, and novel treatments are urgently needed. Apo2 ligand (Apo2L; also tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) has been implicated in antitumor therapy. We found that HTLV-1-infected T-cell lines and primary ATL cells were more resistant to Apo2L-induced apoptosis than uninfected cells. Interestingly, HTLV-1-infected T-cell lines and primary ATL cells constitutively expressed Apo2L mRNA. Inducible expression of the viral oncoprotein Tax in a T-cell line up-regulated Apo2L mRNA. Analysis of the Apo2L promoter revealed that this gene is activated by Tax via the activation of NF-κB. The sensitivity to Apo2L was not correlated with expression levels of Apo2L receptors, intracellular regulators of apoptosis (FLICE-inhibitory protein and active Akt). NF-κB plays a crucial role in the pathogenesis and survival of ATL cells. The resistance to Apo2L-induced apoptosis was reversed by N-acetyl-l-leucinyl-l-leucinyl-l-norleucinal (LLnL), an NF-κB inhibitor. LLnL significantly induced the Apo2L receptors DR4 and DR5. Our results suggest that the constitutive activation of NF-κB is essential for Apo2L gene induction and protection against Apo2L-induced apoptosis and that suppression of NF-κB may be a useful adjunct in clinical use of Apo2L against ATL