Fundamental Steps Involved In Drug Discovery Biology Essay

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Cancer is complex, multi stage disorder. It can be well explained by understanding cell biology and genetics of cell and organism. Currently huge biological and medical research programmes in course. Within the last three decades, molecular oncology has revealed that the genetic and epigenetic alteration had led to the multistage process of cancer growth and progression.

By understanding the molecular mechanism, the more efficacious and less toxic drug approach have been designed to inhibit the specific proteins or abnormal pathway which are generally expressed in cancer cell.

This approach, designated "Target therapy" is applied to many scientific research to discover new targets and to develop new anticancer drug candidates. (Collins and Workman 2006: Weinstein and Joe).

Drug Discovery

The main goal of any cancer drug discovery process is to discover and develop effective and non toxic therapy. This can be achieved by understanding biology of cancer cell and technology. (Suggitt and Bibby 2005).

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The fundamental steps involved in drug discovery are drug identification and validation, clinical identification and clinical studies of Phase I-III, hit-to-lead and lead optimisation.

Since 1955 compounds of both synthetic and natural origin were screened in a panel of cancer cell lines and of mice tumours such as the L1210 leukaemia model.

The development of nude athymic mice and the successful growth of human

tumor xenografts introduced the use of human cancer xenografts in nude mice for

screening purposes in 1976. This observation-driven approach has generated cornerstones

of cancer therapy, including taxol and antracyclines, with the molecular

mechanism of action of these drugs (actually, the target) discovered several years

after the identification of the active compound. As an example, the understanding

of the molecular mechanism of DNA and DNA-interacting proteins allowed to

clarify the mechanism of action of drugs targeting topoisomerases and DNA itself

(e.g. etoposide and platinum derivatives) (Suggitt, et al. 2005).

The target-driven approach to drug discovery stems from the current understanding

of the molecular mechanism underlying cancer development and

progression. The last 25 years of molecular oncology have shown that cancer arises

when the right combination of genetic alterations occurs in a susceptible cell.

Genetic alterations in cancer involve key regulators of vital cell functions, especially

cell cycle and proliferation, apoptosis and cell motility. Proteins aberrantly

expressed in cancer cells as a consequence of genetic alterations may represent

potential targets for cancer drug discovery. Elucidation of the roles of many

kinases, including receptor kinases and signaling kinases, along with the proof that

these enzymes are specifically "druggable" targets, prompted the concept of targetdriven

drug discovery. This "targetcentric" approach to drug discovery can be

described as a linear sequence of steps, starting from the identification of a protein

altered in cancer cells, followed by the development of an assay assessing the

3 Anticancer Drug Discovery and Development 21

biological activity of the target, screening of compounds inhibiting the target and,

after reiterated cycles of optimization and re-testing, identification and selection of

inhibitors, with adequate properties (in terms of potency, specificity, drug-like

properties, preclinical tolerability) to be tested in animals and in humans for antitumor

efficacy and possible toxicological liabilities. (Sager, et al. 2003; Overington,

Al-Lazikani and Hopkins 2006; Green 2004; Pegram, Pietras, Bajamonde, Klein

and Fyfe 2005)

Drug development

The overall success rate of compounds in all therapeutic

areas from phase I clinical trials (first in human) to registration

is 10% (Kola 2008; Kola and Landis 2004). This rate drops to

5% for small molecule oncology therapeutics, the highest

failure rate of all therapeutic areas (along with central nervous

system therapies). Clinical safety and efficacy are the two main

causes for failure of small molecule oncology drugs, each

accounting for approximately 30% of the failures. Drug candidate

terminations due to safety tend to occur early in development

(phases I and II), while those due to lack of efficacy occur

later (phase III)

Considerations and strategies in drug discovery for the purposes

of increasing the probability of success of experimental

small molecule cancer therapeutics in clinical development

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include (1) target validation; (2) compound selectivity analysis

from the perspective of balancing efficacy and toxicity; and

(3) investigation of ancillary means to abrogate toxicity, especially

with respect to undesirable target-related effects. In

oncology, because most of the molecular targets are frequently

involved in various normal physiologic processes as well as in

the disease process, investigational efforts to abrogate toxicity

may be greater, relative to nononcology programs. In other

words, understanding and managing toxicities may be more

important than trying to reduce or eliminate toxicities (which

are more commonly futile)..

Introduction of B16 cells

We analyzed and tried to characterize substance(s) responsible for cytotoxic activities

detected in culture media conditioned by non pigmented B16 melanoma cells (NPB16). The

different cytological tests used showed that ultrafiltrated conditioned media (CM Ul

fraction) contained several cytotoxic factors with a M, lower than 1000 Da. These factors

seemed to act either directly or indirectly on cell membranes, mitochondria, on the cell cycle

and on protein and DNA synthesis. A cytotoxic activity could be found even after high

dilution of CM Ul. These cytotoxic factors were rapidly released by B16 cells in culture,

independently of cell confluence. Their activities in the treated cells were also very fast and

the cytotoxic effects were irreversible after only a few hours of treatment. These factors were

not intermediate products during melanogenesis, neither polyamines, nor proteases. At least

one of them seemed to be a small acidic and basic stable peptide without disulfide bounds

but not heat stable. The synthesis of at least one of these cytotoxic factors was inhibited by

cycloheximide and the cytotoxic activity was partially destroyed by pronase and trypsin, but

not by pepsin.

Many cell types have been shown to release inhibiting or stimulating substances

into their culture medium [l-3]. These activities can regulate growth of cells in

culture, but can also explain invasive capacities of cancer cells in vivo. We

previously showed that mitogenic and cytotoxic soluble factors were released into

serum-free media conditioned by different lines of mouse B16 melanoma cells in

culture [3]. The cytotoxic activity was concentrated in ultrafiltrate Ul (Mw < 1000

Da) prepared from media conditioned by a heterogeneous parental cell line (B16)

and two derived cloned cell lines, containing either non pigmented (NPB16) or

pigmented (Pq16) cells. Ultrafiltrate Ul of the medium conditioned by NPB16 cells

(NPB16 CM IA) was the most cytotoxic [3]. Interestingly, this line was the less

metastatic and less tumorigenic in the mouse [4]. In the present paper, we analyzed

the experimental conditions needed for the production of the cytotoxic factors as

well as some of their characteristics. The conditioned media were generally tested

on non pigmented B16 cells, which were the most sensitive line. First, we investigated

the effects of NPB16 CM Ul on cell proliferation and differentiation as a

function of dilution, duration of treatment or of medium conditioning. Then,

several agents were added during the conditioned media (CM) preparation, in order

to evaluate their effect on the rate of cytotoxicity of these NPB16 CM Ul. We also

tried to determine the nature and some chemical properties of these cytotoxic

factors.

In Vitro Technique

Early attempts to establish predictive tests were dependent on the availability of cell culture techniques in the 1950s. The procedures used included evaluation of cell morphology, exclusion of vital dyes, activity of various enzymes, and incorporation of radioactive precursor molecules after incubation of tumor cells with anticancer agents.8-10 However, subsequent correlative studies showed that only a minority of tests were of predictive value.3,11 Potential problems that may have confounded the predictive value included a lack of standardization and an inability to accurately distinguish growth of malignant and nonmalignant cells in explant cultures from primary tumors. In addition, some assays (e.g., tests for oxygen consumption by tumor cells) proved to be too complicated for routine use.12 Other, more recent techniques continue to be of interest for the prediction of clinical response

In Vivo Techniques

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The two most commonly used in vivo systems to predict clinical drug activity are the subrenal capsule assay and transplantation of tumour cells into nude mice. Advantages of in vivo techniques include the feasibility of testing agents that require metabolic activation and the preservation of three-dimensional tumor structure with cell-cell interactions. Also, drug effects on cell growth can be determined over several cell cycles, and the effects of drug combinations may be studied. Significant disadvantages include the necessity of an animal facility, as well as high costs. Extrapolation of assay results to the clinical setting may be hampered by the fact that treatment in animals is usually started at a low tumor burden while patients usually are treated in an advanced stage when the tumor burden is rather high