Guidelines for clinical evaluation of anti-cancer drugs

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.     

Recent development of oral anti-cancer drugs for breast cancer

Oral anti-cancer drugs play an important role in the treatment of breast cancer. Because these hormonal agents are related to mammary carcinogenesis and tumor growth, they are used not only for therapy but also to prevent the onset of the disease. Tamoxifen, toremifene, fadrozole and other aromatase inhibitors, goserelin, leuprolin and MPA are used widely in Japan as hormonal anti-cancer drugs. In addition oral anti-cancer chemotherapeutic agents, such as cyclophosphamide, 5-FU, 5'-DFUR, FT and UFT are used for breast cancer. The combination of these hormonal and chemotherapeutic agents produces good clinical results in curing the disease. Oral drugs are superior to injected drugs with regard to the QOL of patients.     

The differences of standard therapy for breast cancer between Europe/America and Japan--chemotherapy, operation,and radiotherapy

As increased incidence of breast cancer, the concept of standard therapy based on the evidence based medicine (EBM) has been widely applied to breast cancer treatment in Japan. Since the major parts of evidences are common in Western countries and Japan,general treatment strategy for standard care seems to be identical in both countries. However, there are still some differences due to the limited usages of anti-cancer drugs and supporting drugs. We would discuss about these issues in this paper.     

Participation to international registration trials--from the investigator's standpoint

Clinical developments of new anti-cancer drugs in Japan are far behind from the Western as well as Asian countries, which resulted in much delay for indicating them into Japanese patients. The causes of delay are considered to exist in regulatory authorities, pharmaceutical companies, and investigators, respectively. However, these delays have recently been improved by the revision of Japanese regulatory guidelines with an activity of committee for this issue. After overcoming various issues, two global registration studies involving Japanese institutions have already been initiated and additional global studies are now conducting in the field of gastrointestinal (GI) cancer in Japan. A Japan-Korea joint phase I study of new agent for gastric cancer is also now being conducted. It is time for Japanese GI investigators to recover the delay in new drug development and to make an effort for new evidence originated from Japan.     

Results of questionnaire to 56 medical institutions about clinical trials of cancer chemotherapy]

From the stand point of investigators doing clinical trials of anti-cancer drugs, a questionnaire to survey of the current status of clinical trials concerning on the reactions of medical institutions to the new GCP started in April 1997, sent to 75 institutions all over the Japan. 56 institutions (75%) gave answers to the questionnaire, in August 1998. As the results, apparent decrease of Phase II & III trials were noticed compared the numbers before March 1997. IRB with one or two outside members are well functioned in these institutions. But, training related doctors, nurses (especially CRC) are nowadays most important problems, which are strongly expected to Ministry of Health and Welfare and related medical societies, for instance Japan Society of Clinical Oncology.     

MTT肿瘤药物敏感试验的方法学研究

目的：对MTT法肿瘤药物敏感试验的方法进行选择,旨在建立一种MTT肿瘤药敏试验的规范化操作流程。方法：MTT法测定K562细胞对抗癌药卡铂与紫杉醇的敏感性实验及其影响因素。结果：在每孔K562细胞数为5×10^3（浓度为5×10^4个/ml）、药物作用时间48h、MTT20μl作用6h、单波长570nm处测OD值时,药物对肿瘤细胞的抑制率较高,实验效果较好。结论：规范化的MTT肿瘤药敏试验可以为临床医师开展和实现化疗个体化提供较为可靠的实验依据。     

Biotransformation,a Promising Technology for Anti-cancer Drug Development

With the high morbidity and mortality caused by cancer, finding new and more effective anti-cancer drugs isvery urgent. In current research, biotransformation plays a vital role in the research and development of cancerdrugs and has obtained some achievements. In this review, we have summarized four applications as follows:to exploit novel anti-cancer drugs, to improve existing anti-cancer drugs, to broaden limited anti-cancer drugresources and to investigate correlative mechanisms. Three different groups of important anti-cancer compoundswere assessed to clarify the current practical applications of biotransformation in the development of anti-cancerdrugs.     

Retinoids as anti-cancer agents and their mechanisms of action

Retinoids (vitamin A) have been reported extensively for anti-cancer properties due to their high receptor-binding affinities and gene regulation abilities. However, the anti-cancer potential of retinoids has not been reviewed in recent years. Thus, this review focused on the anti-cancer effects of retinoids and their synergistic effects with other drugs, together with their mechanisms of action in different types of cancers reported in the past five years. The retinoids were well studied in breast cancer, melanoma, and colorectal cancer. Synthetic retinoids have shown higher selectivity, stronger effectiveness, and lower toxicity than endogenous retinoids. Interestingly, the combination treatment of endogenous retinoids with chemotherapy drugs showed enhanced anti-cancer effects. The mechanisms of action reported for retinoids mainly involved the RAR/RXR signaling pathway. However, limited clinical studies were conducted in recent years. Thus, retinoids which are highly potential anti-cancer agents are worth further study in clinical, especially as a combination therapy with chemotherapy drugs.     

抗肿瘤药物相关性心血管疾病的发生机制研究进展

在肿瘤患者的死亡原因中,恶性肿瘤本身导致的死亡为首位原因,其次为抗肿瘤治疗相关性心脏疾病。肿瘤和心血管疾病作为最主要的慢性非传染性疾病,抗肿瘤药物治疗可能导致多种心血管事件,并日益受到关注。抗肿瘤药物包括化疗药物、分子靶向药物和免疫检查点抑制剂,多数可引起不同程度的心血管疾病,称为抗肿瘤药物治疗相关性心脏病。本文重点讨论各种抗肿瘤药物引发心血管疾病的发病机制,为肿瘤研究和临床实践提供参考。     

Epigenetic modulators from “The Big Blue”: A treasure to fight against cancer

Cancer remains a major public health problem in our society. The development of potent novel anti-cancer drugs selective for tumor cells is therefore still required. Deregulation of the epigenetic machinery including DNA methylation, histone modifications and non-coding RNAs is a hallmark of cancer, which provides potential new therapeutic targets. Natural products or their derivatives represent a major class of anti-cancer drugs in the arsenal available to the clinician. However, regarding epigenetically active anti-cancer agents for clinics, the oceans represent a largely untapped resource. This review focuses on marine natural compounds with epigenetic activities and their synthetic derivatives displaying anti-cancer properties including largazole, psammaplins, trichostatins and azumamides.     

Administration of wild-type p53 adenoviral vector synergistically enhances the cytotoxicity of anti-cancer drugs in human lung cancer cells irrespective of the status of p53 gene

Recombinant adenovirus mediated p53 gene transfer combined with anti-cancer drugs has clinical potential for gene therapy of lung cancer. We constructed a recombinant adenoviral vector expressing wild-type p53 cDNA (Ad-p53), and assessed the efficacy of a combined treatment with Ad-p53 and six anti-cancer drugs (cisplatin, 5-fluorouracil, doxorubicin, docetaxel, irinotecan, and etoposide) for human lung cancer cell lines, H1299 (with deleted p53), RERF-LC-OK (with mutant p53), and A549 (with wild-type p53). The infection of the Ad-p53 vector into H1299 cells, RERF-LC-OK cells, or A549 cells increased the sensitivity to all six drugs regardless of the cellular p53 status, and a synergism was observed by the isobolic method in combination studies (D<1). We conclude that our strategy using adenoviral mediated p53 gene transfer to cancer cells can enhance the cytotoxic effect of anti-cancer drugs, which leading to an improvement of lung cancer chemotherapy.     

Examination of anti-emetic effect, safety and usefulness of single oral dose of ondansetron tablet in nausea and emesis induced by anti-cancer drugs--dose-finding study of ondansetron tablet in patients receiving non-platinum anti-cancer drugs]

Inhibitory effects on acute nausea and emesis, safety and usefulness of a single oral dose of Ondansetron tablet were evaluated in 3 different dose levels for comparison by telephone registration system, in patients receiving non-platinum anti-cancer drugs. A single dose of ondansetron at 4 mg, 8 mg or 12 mg was given orally at 2 hrs before the initial administration of anti-cancer drugs. The patients were observed for 24 hours after administration of anti-cancer drugs, for occurrence of nausea and emesis. Efficacy rates of inhibitory effects on nausea and emesis were 83.3% (10/12 cases) in 4 mg dose group, 78.6% (11/14 cases) in 8 mg dose group and 84.6% (11/13 cases) in 12 mg dose group, without statistically significant difference. Side effects were observed in 3 cases (headache, cold feeling and trembling in limbs, sleepiness) in 12 mg dose group, but these symptoms were not severe and disappeared after several hours or several days. No abnormality in clinical laboratory findings attributable to Ondansetron was observed. From the above, it was considered that Ondansetron was a clinically useful anti-emetic for nausea and emesis induced by non-platinum anti-cancer drugs and that 4 mg once daily was the optimal dose.     

人肺癌细胞体外对抗癌药物敏感性的初探

目的探讨人肺癌细胞体外对１０种抗癌药的敏感性及方法的可靠性。方法收集人肺癌手术切除的标本２０例，用一简单、快速，有一定特异性优点的ＭＴＴ（３－（４，５）－双甲基－２－唑噻－（２，５）－二苯基溴化四氮唑蓝）法作威猛、足叶乙甙、阿霉素、长春新碱、长春地辛、卡铂、平阳霉素、氟脲嘧啶、环磷酰胺和异环磷酰胺抗癌敏感药物试验。结果患者不同个体之间药物敏感性不同（Ｐ＜０．０１）：１０种药物平均抑制率以威猛类药物最高（Ｐ＜０．０１），依次为阿霉素、卡铂、足叶乙甙、长春地辛等。敏感药物顺序与临床治疗结果大致相符。结论用ＭＴＴ法可作肿瘤治疗个案化较为可靠的检测方法。     

江西省肿瘤医院抗肿瘤药物不良反应分析

目的 探讨抗肿瘤药物不良反应发生的特点,以减少抗肿瘤药物不良反应的发生,为临床合理用药提供依据.方法 采用系统抽样的方法 ,收集江西省肿瘤医院2013年1月至2015年12月上报于国家药品不良反应监测中心网络平台的413例不良反应(ADR)报告,分别从患者的性别、年龄、药物类别、所累及器官或系统及临床表现等进行统计、分析.结果 413例ADR中男性242例、女性171例;40岁以上中老年患者居多,占86.92％;原患疾病中呼吸系统肿瘤所占比率最高;铂类药物引发的不良反应发生率最高,占23.73％,主要为恶心、呕吐和腹泻;所累及的器官或系统中,消化系统所占比例最高,达24.09％.结论 对抗肿瘤药物不良反应的监测工作应加以重视,做好不良反应的预防及处理,以保证用药安全.     

Cancer chemotherapy of high-age patients with gastrointestinal malignancies

Recently, high aged patients with malignancies have increased in number. When cancer chemotherapy is applied for the high aged patients, kinds or doses of anti-cancer drugs must be more carefully selected or decided than for younger patients, because it is said that the side effects of anti-cancer drugs would easily induce irreversible organ disorders and death in high aged patients. The effects of cancer chemotherapy were compared between high aged patients (over 75 years) and younger patients (5 decade years) with special reference to side effects. The patients underwent cancer chemotherapy were 79.7% of high aged patients and 93.6% of younger. The reasons why cancer chemotherapy was not carried out were high age (5.6% of high aged patients), poor general conditions (7.0% in high aged, 2.3% in younger) and post operative complications (7.0% in high aged, 3.2% in younger). The proportion of patients suffered side effects was almost same in both groups. Dead cases caused by side effects of anti-cancer drugs were 5 in high aged patients (4.4%) and 7 in younger (3.4%). The reason why the proportion of side effects in both groups was not different was that the doses of anti-cancer drugs given for high aged patients were reduced to 80-90% of those for younger patients.     

Drug sensitivity panel of human cancers transplanted in nude mice]

Drug sensitivities of 76 human tumor lines/nude mice to 9 anti-cancer drugs were tested. Human tumor lines include pancreas cancers, brain tumors, neuroblastomas and etc. Tested anti-cancer drugs include MMC, 5-FU, and etc. When clinically equivalent dose of anti-cancer drugs were administered, drug sensitivities of these carcinomas were well correlated with clinical one, although blood brain barrier must be considered when brain tumors were tested. Our drug sensitivity panel revealed that cancers originated from the same organ showed the same tendency of drug sensitivity. Therefore, our drug sensitivity panel is thought to be useful to know the anti-cancer spectrum of newly developed anti-cancer drugs. Our panel is also useful to study the chemotherapy of rare cancers, because clinical studies of rare cancers are difficult. Expression of P-glycoprotein is correlated with drug resistance when treated with CED, but is not correlated with those when treated with MTD (maximum tolerate dose). That is human tumor lines with P-glycoprotein detected by C219 monoclonal antibody showed resistance to ADR, VCR and VLB when treated by CED, but the relationship was not observed when treated with MTD.     

Apoptosis as a measure of chemosensitivity to anti-cancer drugs in gynecological cancer

OBJECTIVE: To examine apoptosis as a measure of chemosensitivity to anti-cancer drugs in gynecological cancer xenografted into nude mice. METHODS: The TUNEL method was used to investigate the induction of apoptosis after exposure to anti-cancer drugs in thirteen gynecological cancers xenografted into nude mice. Moreover, in vivo sensitivities of gynecologic cancer to anti-cancer drugs were determined according to the protocol developed by Battle Laboratories, Columbus, Ohio USA. Both methods were examined for correlation. RESULTS: The apoptosis index by the TUNEL method showed a correlation with the findings using the protocol developed by Battle Laboratories, Columbus, Ohio USA. CONCLUSIONS: Our findings indicate the ability to determine the measure of chemosensitivity by the apoptosis index.     

Prevention of stomatitis induced by anti-cancer drugs

A randomized control trial study was carried out to evaluate the effect of allopurinol mouth wash on stomatitis induced by chemotherapy in gynecologic patients. Chemotherapeutics used consisted of 5-FU+CDDP (PF) given to 10 patients and vincristine and actinomycin-D+cyclophosphamide (VAC) given to 5. Allopurinol mouth wash was prepared for patients to rinse their mouth with the solution 4-5 times daily before and after treatment with anti-cancer drugs. The Japan Society For Cancer Therapy's criteria for stomatitis were used. In the control group, stomatitis occurred in 9 of the 10 patients receiving PF therapy and in all of the 5 receiving VAC. In contrast, stomatitis was observed in only 2 of the 10 patients receiving PF therapy and 2 of the 5 VAC in the allopurinol-treated group. Allopurinol mouth wash showed a marked effect on stomatitis induced by chemotherapy.     

Over-expression of the Beclin1 gene upregulates chemosensitivity to anti-cancer drugs by enhancing therapy-induced apoptosis in cervix squamous carcinoma CaSki cells

The purpose of this study was to investigate whether the autophagy-related gene, Beclin1, plays a role in the regulation of chemosensitivity to anti-cancer drugs in cervical cancer CaSki cells. Expression of the Beclin1 protein was up-regulated in pcDNA3.1-Bec transfectants and led to cell arrest in the G₀/G₁ phase of the cell cycle. The MTT assay indicated that over-expression of Beclin1 sensitized CaSki cells to chemotherapeutic drugs (cisplatin, paclitaxel, 5-fluorouracil, and epirubicin) and induced greater degrees of cytotoxicity than vector-only controls. After treatment with anti-cancer drugs, flow cytometric analysis indicated that the Beclin1-transfected group showed a greater increase in apoptosis than did the non-transfected group. Furthermore, pSUPER-Bec transfectants did not lead to a significant increase of resistance to each of these anti-cancer drugs. These results suggest that Beclin1 plays an important role in the regulation of potent anti-tumor activity, and over-expression of Beclin1 in CaSki cells may enhance apoptosis signaling induced by anti-cancer drugs.     

Clinical application of local hyperthermia combined with antineoplastic agents

At present hyperthermia shows great promise when combined with other modalities. Local thermo-chemotherapy may also be a very attractive research field, but the combination of hyperthermia and anti-cancer drugs is still poorly understood. In this review, the background and the clinical reports on heat and chemotherapy which have been reported during the last year were analyzed. Finally, our clinical experiences with local hyperthermia combined with anti-cancer drugs for gastrointestinal cancer were also reported.