Antimetastatic Activities and Mechanisms of Bisdioxopiperazine Compounds

Abstract

Bisdioxopiperazine (Biz) compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further three bisdioxopiperazine derivatives, bimolane (Bim), probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Since metastases, the prevailing deadliest pathologic feature of cancer in clinics, have been the main obstacle in cancer therapy, antimetastatic effects and mechanisms of Biz compounds are interesting and significant topics of all time for researchers undergoing the investigations of metastases biology, treatments and patho-physiology. This review addresses and highlights the different inhibitions against metastases in vivo and molecular mechanisms in vitro of Biz compounds especially relating to the inhibitions of tumor metastasis including pathways of inhibitions against angiogenesis, topoisomerase II, calmodulin, sialic acid, fibrinogen, cell-movement and so on. We argue hererin that the systematic exploration of antimetastatic activity and mechanisms of Biz compounds seems to be a shortcut for a final solution of cancer therapy in the future.

Anticancer Drug Development, Getting Out from Bottleneck

“…Profit for big manufactures is down. Despite greater fortune spent for the whole process of each anticancer licensing (1-2 billion USD) in US and other developed countries, [11][12][13] cancer therapies improved slightly and are still imperfect in clinical practice, especially for cancer metastasis treatments [3][4][5][6][7][14][15][16][17][18][19][20][21][22]. Thus anticancer drug discoveries and developments are highly risky processes and negative impacts for healthy progresses of drug development and manufacturing worldwide [4][5][6][7][8][9][10][11][12][13].…”

“…Despite steady increases of biology and pathology knowledge towards neoplasm metastasis, their therapeutic efficacy and mechanisms of action by antimetastatic drugs are still not overwhelmed in the past three decades even with state-of-the-art technologies. Few antimetastatic agent or drug exhibits high therapeutic efficacies in cancer patients with neoplasm metastases [3][4][5][6][7][14][15][16][17][18][19][20][21][22]. Even though widely agreed as a top priority and future trend, currently experimental tumor metastatic models are insufficient for successfully harvesting enough effective antimetastatic drugs.…”

“…Despite great advances, current cancer therapy has limitations in many respective, such as high costs of conventional therapy, shortages of highly effective antimetastatic drugs and so on [3][4][5][6][7][8][9][10]. To overcome these obstacles, anticancer drug combination is a useful way to improve therapeutic outcomes in clinical cancer trials [28].…”

“…Despite great advances, current cancer therapy has still many limitations, e.g., high costs for conventional therapy and shortage of effective anticancer and antimetastatic drugs for late-staged cancer patients [3][4][5][6][7]. For this circumstance, great changes in the fields of cancer therapeutic studies are disparately needed.…”

The Relationship between Tumor Sialic Acids and Neoplasm Metastasis and as a Drug Target

“…Clinical anticancer drug therapies currently in use have been mainly focusing on primary tumor growth rather than specifically targeting pathologic courses of metastases relevantly. Finding important drugs targeting specifically to neoplasm metastases is essential and indispensable [4][5][6][7]. It nevertheless needs changing our focus from targeting vascularity and MMPs into more metastatic-relating molecules.…”