Anticancer Drugs Part 1 PDF

The problem Cancer is a leading...

The problem Cancer is a leading - cause of death worldwide, accounting for 9.9 million deaths in 2020. - = 2 ,TE Anticancer Drugs Part 1 Heba Khader, Ph.D Pharmacology 3 s Jay Treatment Cancer arises from one single cell. The transformation from a normal cell into a tumor cell is a multistage process. & A correct cancer diagnosis is essential for adequate and Cancer cells are altered host cells: -g effective treatment because every cancer type requires a ↓ – shorter cell cycle (accelerated) j specific treatment regimen. 2 – excessive proliferation 3 – higher activity of nucleic acid and protein synthesis Treatment ① encompasses one or more modalities such as ② ③ Y – & 1s altered cell-cell communication surgery, and/or radiotherapy, and/or chemotherapy. S – - invasive (disrupt normal healthy tissues) The primary goal is to cure cancer and improving the patient's quality of life. 6 – migration to distant sites - metastasis.‫ كأنها مواطن متمرد قرر يخرب النظام في املدينة‬،‫لكن ملا تصير خلية سرطانية‬.‫ مثل موظف يستعجل في شغله وما يكمل عمله صح‬:‫دورة حياتها قصيرة ومسرعة‬.1.‫ زي شخص يفتح مصانع جديدة في كل مكان بدون أي تخطيط‬:‫تتكاثر بجنون‬.2.‫ كأنها تطلب مواد بناء أكثر من الالزم وتخزنها بشكل عشوائي‬:‫تصنع مواد )حمض نووي وبروتينات( كثير جًدا‬.3.‫ مثل جار ما يتكلم وال يتعاون مع جيرانه‬:‫ما تتواصل مع الخاليا الثانية بشكل طبيعي‬.4.‫ زي شخص يهدم بيوت الناس ويبني مكانها‬:‫تغزو األنسجة السليمة‬.5.‫ كأنها تسافر ملدن ثانية وتبدأ تخرب هناك بعد‬:(”‫تنتقل ألماكن بعيدة )االنتشار أو “االنبثاث‬.6.‫ مما يؤدي إلى مشاكل خطيرة في الجسم كله‬،‫ السرطان هو تمرد خاليا الجسم على النظام‬،‫باختصار‬  Treatment strategies PRINCIPLES OF CANCER CHEMOTHERAPY 1. Goals of treatment: ① ② 289 %s on on as Cause a lethal cytotoxic event or apoptosis in the cancer.. 91 &zi: s ↑ ①– The ultimate goal of chemotherapy is a cure (long-term, disease- - Generally directed toward DNA oor against metabolic sites essential to cell replication – for example, the availability of purines and pyrimidines. - - 3. free survival). 98 is I so si – A true cure requires the eradication of every neoplastic cell. = - 2 · 31554 n Ideally, these anticancer drugs should interfere only with ② – If a cure is not attainable, then the goal becomes control of the cellular processes that are unique to malignant cells. disease (stop the cancer from enlarging and spreading) to Unfortunately, most anticancer drugs do not specifically extend survival and maintain the0 best quality of life (palliative o recognize neoplastic cells but, rather, affect both normal and abnormal cells. therapy). · ⑭ & Treatment strategies 2. Chemotherapy is indicated when: S Cell growth kinetics g w ①– Neoplasms are disseminated and are not amenable to surgery. - Cell growth - fraction is the ②– Also used as a supplemental treatment to attack proportion of cells in the tumor - dividing or preparing to divide. gas micrometastases following surgery and radiation treatment, · is Limit of clinical detection -851 As the tumor enlarge, the cell s (adjuvant chemotherapy). - growth fraction decreases ③ – Prior to the surgical procedure in an attempt to shrink the because a large proportion of 4 · 5351 * cells may not be able to obtain i chemotherapy) cancer (neoadjuvant X X adequate nutrients and blood => => ④ – Also given in low doses to assist in prolonging a remission supply for replication. = im (maintenance chemotherapy). 5 Tumor doubling time is the time Gompertzian Growth Curve for the tumor to double in size. As the tumor gets larger, its , doubling time gets longer. - i -  -9 best coality live Treatment strategies - = - 3. Tumor susceptibility and the growth cycle: – The fraction of tumor cells that are in the replicative cycle (“cell growth fraction”) influences their susceptibility to anticancer agents. – Rapidly dividing cells are generally more sensitive to anticancer drugs, whereas slowly proliferating cells are less sensitive to chemotherapy. In general, nonproliferating cells (those in the G0 phase) - usually survive the toxic effects of many of these - Figure 39.3 Effects of various treatments on the cancer cell burden in a hypothetical patient. = agents. Treatment strategies >>>>> 3. Tumor susceptibility and the growth cycle: Chemotherapeutic agents may be classified according to their reliance on cell cycle kinetics for their cytotoxic effect: a. Cell-cycle specific drugs: are effective only against replicating cells (that is, those cells that are cycling). b. Cell-cycle non-specific drugs: used for replicating and non-replicating cells  Treatment regimens and scheduling The Log-Kill Hypothesis In cancer chemotherapy, destruction of cancer cells follows first- order kinetics (a given dose of drug for a defined time period destroys a constant fraction of cells regardless the absolute number of cells, this is called LOG KILL or fraction kill). A key principle that stems from this finding and that is applicable to hematologic malignancies is an inverse relationship between tumor cell number and curability. Treatment regimens and scheduling Chemotherapy dosing may be based on body weight, body surface area (BSA) or area under the concentration versus time curve (AUC), with an effort being made to tailor the medications to each patient. Log kill BSA is most frequently used because it provides an accurate > comparison of activity and toxicity across species. In addition, BSA correlates with cardiac output, which determine renal and hepatic blood flow and thus affects drug elimination. Dosing adjustments may be required for kidney and liver dysfunction to prevent toxicity. Figure 39.3 Effects of various treatments on the cancer cell burden in a hypothetical patient.  Treatment protocols Treatment protocols Drug combination is more successful than single drug treatment The advantages of combinations: in most cancers. – Provide maximal cell killing within the range of tolerated The following principles are important for selecting appropriate toxicity drugs to use in combination chemotherapy: – Effective against a broader range of cell lines in the (1) Each drug should be active when used alone against the heterogeneous tumor population particular cancer. – May delay or prevent the development of resistant cell lines. (2) The drugs should have different mechanisms of action. Many cancer treatment protocols have been developed, and (3) Cross-resistance between drugs should be minimal. each one is applicable to a particular neoplastic state (4) The drugs should have different toxic effects Cycle Frequency Every 21 days up to 8 cycles Acronyms often are used to designate chemotherapy regimen  Problems associated with Problems associated with chemotherapy chemotherapy A. Resistance: 4. Decreased activation of prodrugs—a Drug resistance is a major problem in cancer chemotherapy. decrease in the activity of the tumor cell Mechanisms of resistance include the following: enzymes needed to convert prodrugs to their 1. Increased DNA repair— ex: alkylating agents and cisplatin. cytotoxic metabolites, ex: 5-fluorouracil. 2. Formation of trapping agents—production of thiol trapping 5. Inactivation of anticancer drugs—most of agents (eg, glutathione). This mechanism of resistance is seen with the purine and pyrimidine antimetabolites. alkylating agents. 6. Decreased drug accumulation 3. Changes in target enzymes—Changes in the drug sensitivity of a This form of multidrug resistance involves the target enzyme, dihydrofolate reductase, and increased synthesis of increased expression of a normal gene the enzyme are mechanisms of resistance of tumor cells to (MDR1) for a cell surface glycoprotein (P- methotrexate. glycoprotein). Problems associated with chemotherapy B. Toxicity: Common adverse effects Therapy also affects normal cells undergoing rapid proliferation (buccal mucosa, bone marrow, Questions? gastrointestinal (GI) mucosa, and hair). 1. Severe vomiting (use antiemetic) 2. Stomatitis 3. Bone marrow suppression 4. Alopecia – occur to a lesser or greater extent during therapy with all antineoplastic agents.