Non-clinical studies for oncology drug development

Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs

Potential mechanisms for Protective Effect of D-Methionine on Plasmid DNA Damage Induced by Therapeutic Carbon Ions

D-methionine (D-Met), a dextrorotatory isoform of the amino acid L-methionine (L-Met), can prevent oral mucositis and salivary hypofunction in mice exposed to radiation. However, the mechanism of its radioprotection is unclear, especially with regard to the stereospecific functions of D-Met. Radiation is known to cause injury to normal tissue by triggering DNA damage in cells. Thus, this study investigated whether the chirality of D-/L-Met affects radiation-induced events at the DNA level. We selected plasmid DNA assays to examine this effect in vitro, as these assays are highly sensitive and allow easy detection of DNA damage. Samples of supercoiled pBR322 plasmid DNA mixed with D-Met, L-Met, or dimethylsulfoxide (DMSO) were prepared and irradiated with a Bragg peak beam of carbon ions (~290 MeV/u) with a 6 cm spread. DNA strand breaks were detected by the change in the form of the plasmid and were subsequently quantified by agarose gel electrophoresis. We found that D-Met yielded approximately equivalent protection from carbon-ion-induced DNA damage as DMSO. Thus, we propose that the protective functions of Met against plasmid DNA damage could be explained by the same mechanism as that for DMSO, namely, hydroxyl radical scavenging. This stereospecific radioprotective mechanism occurred at a level other than DNA level. There was no significant difference between the radioprotective effect of D-Met and L-Met on DNA

Prospective study of atopic status in infants of the cohort in Tokyo, Japan

Several risk factors for the development of allergic diseases are considered including, for example, the level of IgE in cord blood or in the peripheral blood of neonates and the antigenic effect of some foods that are ingested by both babies and mothers during pregnancy and during the lactation period. However, not all infants with atopic diathesis develop allergic diseases. To clarify the risk factors and the mechanism for developing allergic diseases, particularly bronchial asthma (BA), we prospectively investigated atopic diatheses and symptoms in children in a cohort using a questionnaire method. The factors correlated to development of allergic diseases, as a whole, at the age of 5–6 years were atopic family history and any allergic symptom at 4 months of age. However, not all subjects with atopic dermatitis developed BA later on. High levels of total IgE and positive IgE antibody against egg white were not risk factors for developing BA at the age of 5–6 years

GC/MSによる大気粉じん中の水酸化多環芳香族炭化水素の定量

金沢大学理工研究域自然システム学系大気中の粒子状物質（PM）中の水酸化多環芳香族炭化水素（OHPAH）を定量することを目的とするGC/MSによる分析法を開発した．母核の環数が2〜4環のOHPAH 10種を分析対象とし，トリメチルシリル（TMS）誘導体化したうえで検出し，3種類の重水素化，または安定同位体標識化OHPAHを内部標準物質として用いてPM試料の定量に適用した．OHPAHのTMS誘導体の選択イオン検出（SIM）における検出限界（S/N＝3）は，12〜930 fgの範囲で，すべての分析対象物質について10.5分で分離・検出することができた．都市大気標準粉じんや金沢で捕集したPM試料はジクロロメタンで抽出したのち，シリカゲル固相により精製しTMS誘導体化して定量した．金沢で捕集したPM試料中の8種のOHPAHを定量することに成功し，それらの濃度範囲は，20〜4100 fg m−3であり，3-hydroxyfluorantheneのPM中濃度の報告は本研究が初めてである．確立した分析法は，大気粉じん中のOHPAHを定量する際の分析法の選択肢の一つとして有用である．A GC/MS method was developed for the quantification of hydroxylated polycyclic aromatic hydrocarbons (OHPAHs) in airborne particulate matter (PM). Ten OHPAHs having 2 - 4 rings were detected after trimethylsilyl (TMS) derivatization, and the derivatives in PM samples were quantified with three kinds of deuterated or stable isotope labeled OHPAHs as internal standards. The detection limits (S/N = 3) of the derivatives of OHPAHs in the selected ion monitoring (SIM) mode ranged from 12 to 930 fg and all analytes were separated and detected within 10.5 min. A commercially available urban PM sample and PM samples collected in Kanazawa were extracted with dichloromethane, and then the extracts were purified with silica gel solid phase and derivatized OHPAHs in the extracts were quantified. We successfully quantified 8 OHPAHs in PM samples collected in Kanazawa, and their concentrations were in the range of 20 - 4100 fg m−3 and the levels of 3-hydroxyfluoranthene were reported for the first time. This method should be useful as an optional analytical method to quantify OHPAHs in PM samples

Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs

Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs