Antineoplastic Drugs : Treatment Principles and Toxicity

The therapy of cancer has improved dramatically during the past half century. This improvement can be traced to a number of factors: a better understanding of cancer's cause and natural history, better technologies for early detection and diagnosis, improved control of primary tumors through surgery and radiation therapy and more effective drugs. The evolution of drug therapy for cancer has progressed rapidly from alkylating agents and antimetabolites to natural products, and most recently, molecular targeted drugs such as imatinib and gefitinib. As our understanding of the biology of cancer improves, new targets for therapy are being identified daily.


Introduction
ntrone, idarubicin, epirubicin 4) Other antitumor antibiotics-plicamycin, Malignancies arise from excessive cellular actinomycin D, bleomycin proliferation and /or insufficient physiological cell 5) Platinum analogs-cisplatin, carboplatin death.The optimum management of a particular 6) Antimetabolites-methotrexate, cytosine malignancy often involves multimodality therapy, arabinoside, 5-fluuorouracil primarily including surgery, radiation therapy and 7) Miscellaneous-L-asparaginase, hydroxyurea chemotherapy.Surgery and radiation therapy are used All cells, both normal and neoplastic, progress against localized tumors whereas chemotherapy may through the cell cycle which consists of five major be used in management of localized tumors and steps ; systemically disseminated malignant cells.
M-the mitotic phase The growth fraction of a tumor is the proportion disease, after removal of primary tumor.
of tumor cells which are actively replicating, i.e. are 3. Neo-adjuvant treatment, in which the rationale is within the cell replication cycle.Microscopic tumors to reduce the size of primary tumor in order to are usually in the log phase of growth with a high improve the chances of its eradication by other growth fraction whereas macroscopic tumors are in means such as surgery.
the plateau phase with low growth fraction.

Cytotoxic drug classes
Most of the chemotherapy drugs are cell-cycledependent and will be most effective against tumors 1) Alkylating agents-mechlorethamine, chlorawith a high growth fraction.Some of the drugs are cellmbucil, melphalan, cyclophosphamide, cycle-dependent and phase-specific (only kill a busulfan, procarbazine, thiotepa limited number of cells with any single drug exposure) 2) Tubulin-binding agents-vincristine, vinblastine, whereas some are cell-cycle-independent.etoposide, paclitaxel e.g.M phase specific-vincristine, vinblastine, paclitaxel 3) Anthracycline antibiotics-doxorubicin, mitoxa-S phase specific -hydroxyl urea, cytosine arabinoside by reducing the tumor bulk by surgery/ radiotherapy, S phase specific self limiting -6 -mercaptopurine, by using a drug combination including drugs active methotrexate against cells in G phase, or by scheduling drugs to o Cell-cycle-independent alkylating drugs, antitumor synchronize cell populations and increase cell kill.antibiotics cisplatin, Procarbazine Biochemical resistance: Resistance is due to numerous biochemical mechanisms including those Treatment Principles leading to decreased drug accumulation, altered drug Dosing principles: The objective of cytotoxic metabolism, altered drug targets and enhanced nucleic therapy is to use the dose regimen that combines acid repair capacity.e.g. in canine lymphoma, maximum antitumor effect with minimal normal mechanism of resistance is due to increased drug efflux tissue toxicity.Cytotoxic agents follow a first order mediated by P-glycoprotein (a membrane transport kinetics i.e. the same proportion of cells in a tumor is protein confer multiple drug resistance to different killed with each dose.Cytotoxic agents often have a classes anthracycline antibiotics, vinca alkaloids and steep dose response curve and should be used at the taxanes).highest dose possible to achieve highest log cell kill.Pharmacological resistance: It is caused by poor or Agents should be used at the shortest intervals possible erratic drug absorption, metabolism or excretion, or to avoid significant tumor cell repopulation.Dose drug interactions.Some forms of pharmacological and rates are calculated according to body surface area in biochemical resistance may be overcome by increasing square meters as this permits better matching of dose the drug dose, providing that the toxicity to the the to the animal's capacity to metabolize drug than recipient is minimal or non existent at the current dose.dosing per unit of body weight.However, it may be Chemotherapy toxicity appropriate to calculate dose rates according to body weight in Kilograms whereas processes independent Toxicity is the major factor limiting maximum of metabolic rate are important for elimination of drug dose rates.Overall prevalence of chemotherapy drugs such as Melphalan.
induced toxicity has been estimated to be 5-40% for Cytotoxic agents have a small therapeutic index.veterinary patients.Cytotoxic agents are more harmful The recommended dose rate for some drugs is the to rapidly dividing cells.Clinically significant acute maximally tolerated dose rate (MTD).The MTD may toxicity most commonly affects the bone marrow, be defined as the rate that has been shown to result in gastrointestinal system and CNS.mild to moderate but sublethal toxicity in a significant e.g. 1. nitrogen mustard, melphalan -acute myelosuper cent of patients, or serious toxicity to approxippression mately 5% of normal animals of that species.
2. Alkylating agents -oral mucosal ulceration and Drug administration techniques include intestinal denudation systemic administration and local drug administration 3. Ifosfamide-most neurotoxic -altered mental status, (intracavitary injection of liquid formulations, coma, generalized seizures and cerebellar ataxia.intratumoral injections of liquid formulations, Acute, low-grade, non cumulative, non hematologic superficial application of creams and implantations of toxicities lasting 1-3 days, e.g.inappetence or mild slow-release solid formulations).
vomiting, do not usually warrant dose modification.Agent selection: Treatment with multiple drugs is More severe toxicity require 25-50% reduction of the often more effective than single agents and may delay dose or discontinuation of the drug.Clinically or avert the onset of clinical drug resistance.When significant hematologic toxicity usually due to using multiple drugs sequentially or in combination, neutropenia or thrombocytopenia warrants reduction agents used should have activity against specific of drug doses.Subclinical hemolytic toxicity, manifest malignancy and have different or non overlapping as cytopenia on routine blood cell counts, may not dose-limiting toxicities, different mechanism of action require dose requirements.Dysfunction of organs and not be subject to predictable cross resistance.
involved in drug metabolism and excretion, Drug resistance: It may be intrinsic or acquired and principally liver and kidney may warrant drug dose can be categorized in three ways adjustment.Discontinuation of a specific drug should Kinetic resistance: occurs as a result of small growth be considered upon the occurrence of a non-dosefraction.Hence a large primary tumor is in the G phase related toxicity such as anaphylaxis.Discontinuation o -a problem with large primary tumors especially for should be considered of evidence of chronic/cumulative cell-cycle-phase-specific agents.This may be overcome toxicity is found, e.g.doxorubicin-induced cardio-