Strategies for Cancer Treatment

Strategies for Cancer Treatment Cancer is one of the most severe health problems in the world. So the development of new anticancer drugs and new effective strategies to treat cancer is on the rise in drug discovery and clinical therapy. One of the major causes for morbidity and mortality is cancer, alone in 2008 there are approximately 12.7 million cases and 7.6 million deaths worldwide. A diagnosis of cancer goes as back as ca. 460 BC – ca. 370 BC, Hippocrates describes many different types of cancers and referred to them with the word carcinos, Greek word means crab. He gave this name because of the cut surfaces of a solid malignant tumour, showing stretched veins on all sides, similar in appearance of crab. A normal cell changes into a cancer cell due to cell mutation. Stimulatory and inhibitory systems in human body are responsible for controlling cell division. Cancer is monoclonal and for a normal cell to change its â€Å"phenotype† into a â€Å"neoplastic† cell, it has to undergo genetic mutation and these mutations will cause cancer. Carcinogenesis occurs in three stages: initiation, promotion and progression. Malignant transformation occurs at progression step and implies the ability to attack surrounding tissues to spread cancer. DNA damage is one of the main causes of cancer. It can arise from prolong exposure to exogenous agents. Cancer research has generated a rich and complex body of cognition, bring outing cancer to be a disease involving dynamic changes in the genome after a fourth part century of rapid advances. Two types of cancer genes has be outlined in the discovery of mutation, 1st that â€Å"oncogenes with dominant gain of function† and 2nd â€Å"tumor suppressor genes with recessive loss of function†. Both were identified through changes in human and animal cancer cells and by experimental models on the their cancer phenotypes. That tumorigenesis in human beings is a multistep process and that these staircase reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. Cultured cells transform is a multistep process, it was observed that rodent cells show tumorigenic activity after being introduced to a minimum two genetic changes, whereas human cells are more complicate to transform. It has been established by transge nic models of tumorigenesis that tumorigenesis in mice process over multiple rate-limiting steps. In cancer cell genotype, malignant growth consist of six crucial modifications in cell physiology (Figure); self-sufficiency in growth signals, evasion of programmed cell death (apoptosis), insensitivity to growth-inhibitory (antigrowth) signals, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis. Tumor development goes through physiological changes to ensure the anticancer defence mechanism is successfully breached into cells and tissues. These six physiological changes are said to be shared in almost all types of human tumors. Microtubules are new and improved cytotoxic anticancer inhibitors, used in the treatment of different types of cancer. They can attack a cancer cell as a single agent or as combined regiments. â€Å"Microtubule-interacting agents† are of two types, one acts by inhibiting the transformation of tubulin heterodimer into microtubule polymers (â€Å"tubulin polymerisation inhibitors†) and other acts as stabilizing agent, it stabilizes the microtubule under normal destabilize conditions (â€Å"microtubule stabilizers†). Vincristine and Vinblastine agents are used for tubulin polymerization inhibitor. They were approved by FDA in 1963 and 1965. The 1st agent to use as microtubule-stabilizing agent was paclitaxel (or taxol) and was approved by FDA in 1992 and then semi-synthetic analog docetaxel in 1996. The use of microtubule-stabilizing agents as anticancer drugs has made a significant advance in cancer treatment. Taxol is a complex diterpene. Wall, Wani and co-workers were the first to isolate it from the bar of the pacific yew tree Taxus brevifolia Nutt in 1971. The compound showed excellent in vivo antitumor activity in nude mice experiment modelled as human tumour, which initiated the preclinical formulation and studies on Taxol toxicity in 1977 by NCI (National Cancer Institute). Susan Horwitz and co-workers were the 1st to identify the microtubule-stabilising properties of Taxol. They also identified the mechanism of action of taxol which stabilises the cellular microtubules is distinct from other compounds. Since 1995 many more natural products which share same properties as taxol i.e. depolymerisation of microtubules has been discovered. Cellular targets of microtubules-stabilizing agents consist of hollow filaments of ca.240 Ã… diameter, they are made of 55 kD proteins ÃŽ ±- and ÃŽ ²-tubulin as an important subunit. Cytoskeleton consists of actin polymers and intermediate filaments, however microtubules are one of the essential components and responsible for various cellular functions, such as maintenance of cell shape, its development and motility, intracellular transport of vesicles. Cellular microtubules are made of 13 protofliaments â€Å"(i.e. linear polymer with head-to-tail arrangement of ÃŽ ±- and ÃŽ ²-tubulin subunits)† There are possibilities structures with different protofilaments number, however only the structure with 13 protofilaments can align ÃŽ ±- and ÃŽ ²-tubulin parallel along with the axis of microtubules cylinder and this can cellular transport by motor proteins over a long distance. Microtubules has the ability to shorten and lengthen its length by adding or losing ÃŽ ±/ÃŽ ² tubulin from microtubule ends, and this known as â€Å"dynamic instability†. The dynamic properties of the microtubules are responsible for proper assembly of the mitotic spindle and the sister chromatids movement to the spindle poles. The spindle microtubules are 4-100 folds more dynamic as compare to the one’s forming interphase cytoskeleton. As mentioned above microtubule-interacting agents are of two types, one inhibits the microtubule polymerisation or destabilise the microtubules which already exists â€Å"(such as Vinca alkaloids or colchicines)† and other stabilise microtubules under destabilising conditions. Both types of agents would lead intense cell cycle arrest in mitosis at cellular level and would bring death that cell through apoptpsis. According to the research done by Horwitz and co-workers it is established that if a human cancer cell is treated with low concentration of microtubule-stabilising drugs, this will lead to abnormal mitosis formation, followed by the cell cycle arrest in G1 and eventually apoptosis will take place in arrested G1 state. However if high concentration of drug is used against human cancer cell, it will cause a prolong mitotic block and cells will exit without multiplying, as a result formation of tetraploid G1 cells will take place, which then leads to cell apoptosis. This can be established from the these results that it is a fundamental requirement for the cells to go through mitosis to achieve apoptosis by microtubule-stabilizing agents. For anticancer drugs, the cellular response to MSA’s can be modify due to changes occur in the cells and can lead to drug resistance or cell may be inherently acquired resistance against the effects of growth inhibitors due to the resistance protein. Drug efflux by ABC transporters such as the phosphoglycp-protein (P-gp), is one of the most often drug resistance observed in the cancer cells. Introduction of taxol was given above, now we will look at in more detail. Taxol showed excellent in vivo antitumor activity in nude mice experiment modelled as human tumour, which initiated the preclinical formulation and studies on Taxol toxicity in 1977 by NCI (National Cancer Institute). Susan Horwitz and co-workers were the 1st to identify the microtubule-stabilising properties of Taxol. They also identified the mechanism of action of taxol which stabilises the cellular microtubules is distinct from other compounds. Anticancer drugs from taxol are used widely to treat different types of cancer such as ovarian, breast and non-small cell lungs cancer. It can be used on its own, monotherapy or combined with cis-platin. Taxol has very low stability and formulation difficulties, however one of the major issue in it development is its low availability from natural sources.