**Author details**

combination with traditional chemotherapies [70, 71]. However, one would not expect in the first instance that angiogenic inhibitors might reduce the intratumoral delivery of cytotoxic agents (traditional chemotherapy) by decreasing perfused blood vessels with impaired blood flow and decrease drug transport in treated tumor cells [48, 72]. It would also increase tissue hypoxia and inhibit tumor cell proliferation although proliferating cells are an easy target for

312 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

To overcome such hurdles and to enhance synergistic therapeutic potential of chemo and anti-angiogenic drugs when used in combination, Kerbel proposed three mechanistic approaches in this scenario to be adopted; first, normalization of tumor microvessels by anti-angiogenic compounds [73, 74]; second, maximum tolerated dose chemotherapy during the break periods of successive courses [72, 75], and third, use of known chemotherapeutic agents having anti-angiogenic effects [72]. The additional advantages of chemotherapy while improving their anti-angiogenic effects may be grabbed by adopting "metronomic chemotherapy" which states that "the administration of chemotherapeutic agents at relatively low, minimally toxic doses on a frequent schedule of administration at regular close intervals, with no prolonged drug-free breaks [76, 77]." By such approaches, endothelial cells are directly killed, and progenitor ECs are suppressed in circulation. Furthermore, minimal use of toxic doses lowers the frequency of adverse events in treated patients [72, 76, 77]. Such treatment strategies may be adopted for a prolonged period of time with angiogenic inhibitors in the treatment of advanced solid tumors with little side effects as validated by phase II clinical trials; however, phase III clinical studies are exten-

In vivo, in vitro, and in ova assays for angiogenesis assessment are the reliable approaches in basic research and to some extent in real-world clinical practices. However, in vivo systems are difficult to perform and time consumable, and the process of quantification is much complicated than in vitro assays. Conversely, these are relatively better due to complex nature of the vascular response to the test compound. In vitro angiogenesis assays may perform in a short period and provide the accurate and reliable outcome of angiogenic processes. Mouse models based angiogenesis assays have also standardized to an improved understanding of tumor angiogenesis and lymphangiogenesis. Similarly, such models are also used to assess vasculogenesis and arteriogenesis in ischemic heart diseases, blindness, psoriasis, and arthritis. Angiogenesis assessment always plays a focal role to determine the pathogenesis and progression of certain challenging diseases in human populations in particular human cancer. An ample understanding of angiogenesis research in tumor progression, by knowing the molecular mechanisms and cellular pathways, also opens the ways to design and develop effective anti-angiogenic inhibitors. The manipulation of the human genome in a precise and predictable manner due to recently developed molecular techniques has opened new gates for the generation of more reliable models for angiogenesis studies and the testing of new

chemotherapy [48, 72].

sively demanded in this direction [70, 71].

**9. Conclusions**

therapeutic strategies.

Imran Shahid¹, ²\*, Waleed H. AlMalki¹, Mohammed W. AlRabia³, Muhammad Ahmed¹, Mohammad T. Imam4 , Muhammed K. Saifullah5 and Muhammad H. Hafeez6

\*Address all correspondence to: iyshahid@uqu.edu.sa

1 Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia

2 Applied and Functional Genomics Laboratory, Center of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan

3 Department of Medical Microbiology, College of Medicine, King Abdul Aziz University, Jeddah, Saudi Arabia

4 Department of Clinical Pharmacy, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia

5 Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia

6 Department of Gastroenterology and Hepatology, Fatima Memorial College of Medicine and Dentistry, Shadman, Lahore, Pakistan

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