Section IX - Chemotherapy of Neoplastic Diseases ppsx

Section IX. Chemotherapy of Neoplastic Diseases Introduction Among the subspecialties of internal medicine, medical oncology may have had the greatest impact in changing the practice of medicine in the past four decades, as curative treatments have been identified for a number of previously fatal malignancies such as testicular cancer, lymphomas, and leukemia. New drugs have entered clinical use for disease presentations previously either untreatable or amenable to only local means of therapy, such as surgery and irradiation. At present, adjuvant chemotherapy routinely follows local treatment of breast cancer, colon cancer, and rectal cancer, and chemotherapy is employed as part of a multimodality approach to the initial treatment of many other tumors, including locally advanced stages of head and neck, lung, cervical, and esophageal cancer, soft tissue sarcomas, and pediatric solid tumors. The basic approaches to cancer treatment are constantly changing. Clinical protocols are now exploring genetic therapies, manipulations of the immune system, stimulation of normal hematopoietic elements, induction of differentiation in tumor tissues, and inhibition of angiogenesis. Research in each of these new areas has led to experimental or, in some cases, routine applications for both malignant and nonmalignant disease. The same drugs used for cytotoxic antitumor therapy have become important components of immunosuppressive regimens for rheumatoid arthritis (methotrexate and cyclophosphamide), organ transplantation (methotrexate and azathioprine), sickle cell anemia (hydroxyurea), antiinfective chemotherapy (trimetrexate and leucovorin), and psoriasis (methotrexate). Thus, a broad spectrum of medical, surgical, and pediatric specialists employ these drugs for both neoplastic and nonneoplastic disease. At the same time, few categories of medication in common use have a narrower therapeutic index and a greater potential for causing harmful side effects than do the antineoplastic drugs. A thorough understanding of their pharmacology, drug interactions, and clinical pharmacokinetics is essential for safe and effective use in human beings. Traditionally, cancer drugs were discovered through large-scale screening of synthetic chemicals and natural products against animal tumor systems, primarily murine leukemias. The agents discovered in the first two decades of cancer chemotherapy (1950 to 1970) largely interacted with DNA or its precursors, inhibiting the synthesis of new genetic material or causing irreparable damage to DNA itself. An overview of such agents is given in Figure IX–1. In recent years, the discovery of new agents has extended from the more conventional natural products such as paclitaxel and semisynthetic agents such as etoposide, both of which target the proliferative process, to entirely new fields of investigation that represent the harvest of new knowledge about cancer biology. The first successful applications of this knowledge include diverse drugs. One agent, interleukin-2, regulates the proliferation of tumor-killing T lymphocytes and so-called natural killer cells; this agent has proven able to induce remissions in a fraction of patients with malignant melanoma and renal cell carcinoma, diseases unresponsive to conventional drugs. Another agent, all-trans-retinoic acid, elicits differentiation and can be used to promote remission in acute promyelocytic leukemia, even after failure of standard chemotherapy. The related compound 13- cis-retinoic acid prevents occurrence of second primary tumors in patients with head and neck cancer. Initial success in characterizing unique tumor antigens and oncogenes has introduced new possible therapeutic opportunities based on an understanding of tumor biology. Thus the bcr-abl translocation in chronic myelocytic leukemia codes for a tyrosine kinase essential to cell proliferation and survival. Inhibition of the kinase by imatinib (STI-571), a new molecularly targeted drug, has produced a high response rate in chronic-phase patients resistant to standard therapy. In a similar, though immunological, approach tumor-associated antigens, such as the her- 2/neu receptor in breast cancer cells, have become the target for monoclonal antibody therapy that has shown activity in patients. These examples emphasize that the care of cancer patients is likely to undergo revolutionary changes as entirely new treatment approaches are identified, based on new knowledge of cancer biology (Kaelin, 1999). The diversity of agents useful in treatment of neoplastic disease is summarized in Table IX–1. The classification used in Chapter 52: Antineoplastic Agents, which follows, is a convenient framework for describing various types of agents. Figure IX–1. Summary of the Mechanisms and Sites of Action of Chemotherapeutic Agents Useful in Neoplastic Disease. PALA =N- phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate. It is unlikely that new therapies will totally replace existing drugs, as these drugs have become increasingly effective and their toxicities have become more manageable and predictable in recent years. Improvements in their use are the result of a number of factors, including the following: 1. Drugs now are routinely used earlier in the course of the patient's management, often in conjunction with radiation or surgery, to treat malignancy when it is most curable and when the patient is best able to tolerate treatment. Thus, adjuvant therapy and neoadjuvant chemotherapy are used in conjunction with irradiation and surgery in the treatment of head and neck, esophageal, lung, and breast cancer patients. 2. The availability of granulocyte colony-stimulating factor (G-CSF; see Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins) has shortened the period of leukopenia after high-dose chemotherapy, increasing the safety of bone marrow–ablative regimens and decreasing the incidence of life-threatening infection. A similar megakaryocyte growth and development factor has been cloned but has not yet achieved a useful place as an adjunct to chemotherapy. 3. A greater insight into the mechanisms of tumor cell resistance to chemotherapy has led to the more rational construction of drug regimens and the earlier use of intensive therapies. Drug-resistant cells may be selected from the larger tumor population by exposure to low-dose, single-agent chemotherapy. The resistance that arises may be specific for the selecting agent, such as the deletion of a necessary activating enzyme (deoxycytidine kinase for cytosine arabinoside), or more general, such as the overexpression of a general drug-efflux pump such as the P-glycoprotein, a product of the MDR gene. This membrane protein is one of several ATP-dependent transporters that confer resistance to a broad range of natural products used in cancer treatment. More recently, it has become appreciated that mutations underlying malignant transformation, such as the loss of the p53 suppressor oncogene, may lead to drug resistance. (A suppressor gene is essential for normal control of cell proliferation; its loss or mutation allows cells to undergo malignant transformation.) Mutation of p53, or its loss, or the overexpression of the bcl-2 gene that is translocated in nodular non-Hodgkin's lymphomas, inactivates a key pathway of programmed cell death (apoptosis) and leads to survival of highly mutated tumor cells that have the capacity to survive DNA damage. Drug discovery efforts are now directed toward restoring apoptosis in tumor cells, as this process, or its absence, seems to have profound influence on tumor cell sensitivity to drugs. Each of these topics concerning drug resistance is covered in greater detail in Chapter 52: Antineoplastic Agents. In designing specific regimens for clinical use, a number of factors must be taken into account. Drugs are generally more effective in combination and may be synergistic through biochemical interactions. These interactions are useful in designing new regimens. It is more effective to use drugs that do not share common mechanisms of resistance and that do not overlap in their major toxicities. Drugs should be used as close as possible to their maximum individual doses and should be given as frequently as possible to discourage tumor regrowth and to maximize dose intensity (the dose given per unit time, a key parameter in the success of chemotherapy). Since the tumor cell population in patients with visible disease exceeds 1 g, or 10 9 cells, and since each cycle of therapy kills less than 99% of the cells, it is necessary to repeat treatments in multiple cycles to kill all the tumor cells. The Cell Cycle An understanding of cell-cycle kinetics is essential for the proper use of the current generation of antineoplastic agents. Many of the most potent cytotoxic agents act by damaging DNA. Their toxicity is greater during the S, or DNA synthetic, phase of the cell cycle, while others, such as the vinca alkaloids and taxanes, block the formation of the mitotic spindle in M phase. These agents have activity only against cells that are in the process of division. Accordingly, human neoplasms that are currently most susceptible to chemotherapeutic measures are those with a high percentage of cells undergoing division. Similarly, normal tissues that proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) are subject to damage by most antineoplastic drugs, and such toxicity often limits the usefulness of drugs. On the other hand, slowly growing tumors with a small growth fraction (for example, carcinomas of the colon or lung) often are unresponsive to cytotoxic drugs. Although differences in the duration of the cell cycle occur between cells of various types, all cells display a similar pattern during the division process. This cell cycle may be characterized as follows (see Figure IX–2): (1) There is a presynthetic phase (G 1 ); (2) the synthesis of DNA occurs (S); (3) an interval follows the termination of DNA synthesis, the postsynthetic phase (G 2 ); and (4) mitosis (M) ensues—the G 2 cell, containing a double complement of DNA, divides into two daughter G 1 cells. Each of these cells may immediately reenter the cell cycle or pass into a nonproliferative stage, referred to as G 0 . The G 0 cells of certain specialized tissues may differentiate into functional cells that no longer are capable of division. On the other hand, many cells, especially those in slow-growing tumors, may remain in the G 0 state for prolonged periods, only to reenter the division cycle at a later time. Damaged cells that reach the G 1 /S boundary undergo apoptosis, or programmed cell death, if the p53 gene is intact and if it exerts its normal checkpoint function. If the p53 gene is mutated and the checkpoint function fails, damaged cells will not be diverted to the apoptotic pathway. These cells will proceed through S phase and some will emerge as a drug- resistant population. Thus, an understanding of cell-cycle kinetics and the controls of normal and malignant cell growth is crucial to the design of current therapy regimens and the search for new drugs. Figure IX–2. The Cell Cycle and the Relationship of Antitumor Drug Action to the Cycle. G 1 is the period between mitosis and the beginning of DNA synthesis. Resting cells (cells that are not preparing for cell division) are said to be in a subphase of G 1 , G 0 . S is the period of DNA synthesis; G 2 the premitotic interval; and M the period of mitosis. Examples of cell-cycle–dependent anticancer drugs are listed in blue below the phase in which they act. Drugs that are cytotoxic for cells at any point in the cycle are called cycle-phase-nonspecific drugs. (Modified from Pratt et al. , 1994 with permission.) Achieving Therapeutic Balance and Efficacy While not the subject of this chapter, it must be emphasized that the treatment of most cancer patients requires a skillful interdigitation of multiple modalities of treatment, including surgery, irradiation, and drugs. Each of these forms of treatment carries its own risks and benefits. It is obvious that not all drugs and not all regimens are safe or appropriate for all patients. Numerous factors must be considered, such as renal and hepatic function, bone marrow reserve, and the status of general performance and accessory medical problems. Beyond those considerations, however, are less quantifiable factors such as the likely natural history of the tumor being treated, the patient's willingness to undergo harsh treatments, the patient's physical and emotional tolerance for side effects, and the likely long-term gains and risks involved. The emphasis in Chapter 52: Antineoplastic Agents is placed upon the drugs, but it is essential to point out the importance of the role played by the patient. It is generally agreed that patients in good nutritional state and without severe metabolic disturbances, infections, or other complications have better tolerance for chemotherapy and have a better chance for significant improvement than do severely debilitated individuals. Ideally, the patient should have adequate renal, hepatic, and bone marrow function, the latter uncompromised by tumor invasion, previous chemotherapy, or irradiation (particularly of the spine or pelvis). Nevertheless, even patients with advanced disease have improved dramatically with chemotherapy. Although methods that would enable accurate prediction of the responsiveness of a particular tumor to a given agent are still investigational, in the future, molecular studies of tumor specimens may allow prediction of response and the rational selection of patients for specific drugs. Despite efforts to anticipate the development of complications, anticancer agents have variable pharmacokinetics and toxicity in individual patients. The causes of this variability are not always clear and often may be related to interindividual differences in drug metabolism, drug interactions, or bone marrow reserves. In dealing with toxicity, the physician must provide vigorous supportive care, including, where indicated, platelet transfusions, antibiotics, and hematopoietic growth factors (see Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins). Other delayed toxicities affecting the heart, lungs, or kidneys may not be reversible and may lead to permanent organ damage or death. Fortunately, such toxicities will be uncommon if the physician adheres to standard protocols and respects the guidelines for drug usage detailed in the following discussion. Chapter 52. Antineoplastic Agents Alkylating Agents History Although synthesized in 1854, the vesicant properties of sulfur mustard were not described until 1887. During World War I, medical attention was first focused on the vesicant action of sulfur mustard on the skin, eyes, and respiratory tract. It was appreciated later, however, that serious systemic toxicity also follows exposure. In 1919, Krumbhaar and Krumbhaar made the pertinent observation that the poisoning caused by sulfur mustard is characterized by leukopenia and, in cases that came to autopsy, by aplasia of the bone marrow, dissolution of lymphoid tissue, and ulceration of the gastrointestinal tract. In the interval between World Wars I and II, extensive studies of the biological and chemical actions of the nitrogen mustards were conducted. The marked cytotoxic action on lymphoid tissue prompted Gilman, Goodman, and T.F. Dougherty to study the effect of nitrogen mustards on transplanted lymphosarcoma in mice, and in 1942 clinical studies were initiated. This launched the era of modern cancer chemotherapy (Gilman, 1963). In their early phases, all these investigations were conducted under secrecy restrictions imposed by the use of classified chemical-warfare agents. At the termination of World War II, however, the nitrogen mustards were declassified; a general review was presented by Gilman and Philips (1946). A more recent review is provided by Ludlum and Tong (1985). Thousands of variants of the basic chemical structure of the nitrogen mustards have been prepared, but only a few of these agents have proven more useful than the original compound in specific clinical circumstances (see below). At present five major types of alkylating agents are used in the chemotherapy of neoplastic diseases: (1) the nitrogen mustards, (2) the ethylenimines, (3) the alkyl sulfonates, (4) the nitrosoureas, and (5) the triazenes. Chemistry The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents and may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine and pyrimidine bases of DNA—particularly, the 1 and 3 nitrogens of adenine, the 3 nitrogen of cytosine, and the 6 oxygen of guanine—also may be alkylated, as will be the phosphate atoms of the DNA chains and amino and sulfhydryl groups of proteins. To illustrate the actions of alkylating agents, possible consequences of the reaction of mechlorethamine (nitrogen mustard) with guanine residues in DNA chains are shown in Figure 52– 1. First, one 2-chloroethyl side chain undergoes a first-order (S N 1) intramolecular cyclization, with release of Cl – and formation of a highly reactive ethyleniminium intermediate (Figure 52– 1A). By this reaction, the tertiary amine is converted to an unstable quaternary ammonium compound, which can react avidly, through formation of a carbonium ion or transition complex intermediate, with a variety of sites that possess high electron density. This reaction proceeds as a second-order (S N 2) nucleophilic substitution. Alkylation of the 7 nitrogen of guanine residues in DNA (Figure 52– 1B), a highly favored reaction, may exert several effects of considerable biological importance. Normally, guanine residues in DNA exist predominantly as the keto tautomer and readily make Watson–Crick base pairs by hydrogen bonding with cytosine residues. However, when the 7 nitrogen of guanine is alkylated (to become a quaternary ammonium nitrogen), the guanine residue is more acidic and the enol tautomer is favored. The modified guanine can mispair with thymine residues during DNA synthesis, leading to the substitution of an adenine–thymine base pair for a guanine–cytosine base pair. Second, alkylation of the 7 nitrogen labilizes the imidazole ring, making possible the opening of the imidazole ring or depurination by excision of guanine residues. Either of these seriously damages the DNA molecule and must be repaired. Third, with bifunctional alkylating agents, such as nitrogen mustard, the second 2-chloroethyl side chain can undergo a similar cyclization reaction and alkylate a second guanine residue or another nucleophilic moiety, resulting in the cross-linking of two nucleic acid chains or the linking of a nucleic acid to a protein, alterations that would cause a major disruption in nucleic acid function. Any of these effects could adequately explain both the mutagenic and the cytotoxic effects of alkylating agents. However, cytotoxicity of bifunctional alkylators correlates very closely with interstrand cross-linkage of DNA (Garcia et al. , 1988). Figure 52–1. Mechanism of Action of Alkylating Agents. The ultimate cause of cell death related to DNA damage is not known. Specific cellular responses include cell-cycle arrest, DNA repair, and apoptosis, a specific form of nuclear fragmentation termed programmed cell death (Fisher, 1994). The p53 gene product senses DNA damage and initiates apoptosis in response to DNA alkylation. Mutations of p53 lead to alkylating-agent resistance (Kastan, 1999). All nitrogen mustards are chemically unstable but vary greatly in their degree of instability. Therefore, the specific chemical properties of each member of this class of drugs must be considered individually in therapeutic applications. For example, mechlorethamine is very unstable, and it reacts almost completely in the body within a few minutes of its administration. By contrast, agents such as chlorambucil are sufficiently stable to permit oral administration. Cyclophosphamide requires biochemical activation by the cytochrome P450 system of the liver before its cytotoxicity becomes evident. The ethylenimine derivatives such as chlorambucil and melphalan react by an S N 2 reaction; since the opening of the ethylenimine intermediate is acid-catalyzed, they are more reactive at acidic pH. Structure–Activity Relationship The alkylating agents used in chemotherapy encompass a diverse group of chemicals that have in common the capacity to contribute, under physiological conditions, alkyl groups to biologically vital macromolecules such as DNA. In most instances, physical and chemical parameters, such as lipophilicity, capacity to cross biological membranes, acid dissociation constants, stability in aqueous solution, and sites of macromolecular attack, determine drug activity in vivo. With several of the most valuable agents (e.g., cyclophosphamide and the nitrosoureas), the active alkylating moieties are generated in vivo after complex metabolic reactions. The nitrogen mustards may be regarded as nitrogen analogs of sulfur mustard. The biological activity of both types of compounds is based upon the presence of the bis-(2-chloroethyl) grouping. While mechlorethamine has been widely used in the past, various structural modifications have resulted in compounds with greater selectivity and stability and therefore less toxicity. Bis-(2- chloroethyl) groups have been linked to amino acids (phenylalanine), substituted phenyl groups (aminophenyl butyric acid, as in chlorambucil), pyrimidine bases (uracil), and other chemical entities in an effort to make a more stable and orally available form. Although none of these modifications has produced an agent highly selective for malignant cells, some have unique pharmacological properties and are more useful clinically than is mechlorethamine. Their structures are shown in Figure 52–2. Figure 52–2. Nitrogen Mustards Employed in Therapy. The addition of substituted phenyl groups has produced a series of relatively stable derivatives that retain the ability to form reactive charged intermediates; the electron-withdrawing capacity of the aromatic ring greatly reduces the rate of cyclization and carbonium ion formation, and these compounds therefore can reach distant sites in the body before reacting with components of blood and other tissues. Chlorambucil and melphalan are the most successful examples of such aromatic mustards. These compounds can be administered orally if desired. A classical example of the role of host metabolism in the activation of an alkylating agent is seen with cyclophosphamide—now the most widely used agent of this class. The design of this molecule was based on two considerations. First, if a cyclic phosphamide group replaced the N-methyl of mechlorethamine, the compound might be relatively inert, presumably because the bis-(2- chloroethyl) group of the molecule could not ionize until the cyclic phosphamide was cleaved at the phosphorus–nitrogen linkage. Second, it was hoped that neoplastic tissues might possess high phosphatase or phosphamidase activity capable of accomplishing this cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. In accord with these predictions, the parent cyclophosphamide displays only weak cytotoxic, mutagenic, or alkylating activity in vitro and is relatively stable in aqueous solution. However, when administered to experimental animals or patients bearing susceptible tumors, it causes marked chemotherapeutic effects, as well as mutagenicity and carcinogenicity. The postulated role for phosphatases or phosphamidases in the mechanism of action of cyclophosphamide has proven incorrect. Rather, the drug undergoes metabolic activation (hydroxylation) by the cytochrome P450 mixed-function oxidase system of the liver (Figure 52–3), with subsequent transport of the activated intermediate to sites of action, as discussed below. The selectivity of cyclophosphamide against certain malignant tissues may result in part from the capacity of normal tissues, such as liver, to protect themselves against cytotoxicity by further degrading the activated intermediates via aldehyde dehydrogenase and other pathways. Figure 52–3. Metabolism of Cyclophosphamide. Ifosfamide is an oxazaphosphorine, similar to cyclophosphamide. Cyclophosphamide has two chloroethyl groups on the exocyclic nitrogen atom, whereas one of the two chloroethyl groups of ifosfamide is on the cyclic phosphamide nitrogen of the oxazaphosphorine ring. Like cyclophosphamide, ifosfamide is activated in the liver by hydroxylation. However, the activation of ifosfamide proceeds more slowly, with greater production of dechlorinated metabolites and chloroacetaldehyde. These differences in metabolism likely account for the higher doses of ifosfamide required for equitoxic effects and the possible differences in antitumor spectrum of the two agents. Although initially considered an antimetabolite, the triazene derivative 5-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide, usually referred to as dacarbazine or DTIC, functions through alkylation. Its structural formula is shown below: [...]... as 1,3-bis-(2-chloroethyl )-1 -nitrosourea (carmustine, BCNU), 1-( 2-chloroethyl )-3 -cyclohexyl-1-nitrosourea (lomustine, CCNU), and its methyl derivative (semustine, methyl-CCNU), as well as the antibiotic streptozocin (streptozotocin), exert their cytotoxicity through the spontaneous breakdown to alkylating and carbamoylating moieties The structural formula of carmustine is as follows: The antineoplastic... cause extensive cross-linkage, and DNA breakdown occurs Specific repair enzymes for removing alkyl groups from the O-6 of guanine (guanine O6-alkyl transferase) and the N-3 of adenine and N-7 of guanine (3-methyladenine-DNA glycosylase) have been identified (Matijasevic et al., 1993) The presence of sufficient levels of guanine O6-alkyl transferase protects cells from cytotoxic effects of nitrosoureas and... progresses to the synthesis of thymidylate by transfer of the methylene group and two hydrogen atoms from folate to dUMP, this reaction is blocked in the inhibitory complex by the stability of the fluorine carbon bond on FdUMP; sustained inhibition of the enzyme results (Santi et al., 1974) Figure 52–10 Site of Action of 5-Fluoro-2'-Deoxyuridine-5'-Phosphate (5FdUMP) 5-FU, 5-fluorouracil; dUMP, deoxyuridine... same time interferes drastically with certain other aspects of pyrimidine action A number of 5-FU analogs have reached the clinic The most important of these is capecitabine (N4-pentoxycarbonyl-5'-deoxy-5-fluorocytidine), a drug with proven activity against colon and breast cancers This orally administered agent is converted to 5'-deoxy-5-fluorocytidine by carboxylesterase activity in liver and other... crucial for antineoplastic activity involves reduction of the diphosphate nucleotide by the enzyme ribonucleotide diphosphate reductase to the deoxynucleotide level and the eventual formation of 5-fluoro-2'-deoxyuridine-5'-phosphate (FdUMP) 5-FU also may be converted directly to the deoxyriboside 5-FUdR by the enzyme thymidine phosphorylase and further to F-dUMP, a potent inhibitor of thymidylate synthesis,... General Mechanism of Action The best-characterized agents in this class are the halogenated pyrimidines, a group that includes fluorouracil (5-fluorouracil, or 5-FU), floxuridine (5-fluoro-2'-deoxyuridine, or 5-FUdR), and idoxuridine (5-iodode-oxyuridine; see Chapter 50: Antimicrobial Agents: Antiviral Agents (Nonretroviral)) If one compares the van der Waals radii of the various 5-position substituents,... that of C—H and prevents the methylation of the 5 position of 5-FU by thymidylate synthase Instead, in the presence of the physiological cofactor 5,10-methylene tetrahydrofolate, the fluoropyrimidine locks the enzyme in an inhibited state Thus, substitution of a halogen atom of the correct dimensions can produce a molecule that sufficiently resembles a natural pyrimidine to interact with enzymes of pyrimidine... methotrexate is used as part of the combination therapy of Burkitt's and other non-Hodgkin's lymphomas and carcinomas of the breast, head and neck, ovary, and bladder High-dose methotrexate, with leucovorin rescue, can cause substantial tumor regression in osteosarcoma and in combination therapy of leukemias and non-Hodgkin's lymphomas A 6- to 72-hour infusion of relatively large amounts of methotrexate may... converted by hepatic mixed-function oxygenases (Ng and Waxman, 1991), are capable of forming DNA cross-links The aziridine rings open after protonation of the ring-nitrogen, leading to a reactive molecule Absorption, Fate, and Excretion TEPA becomes the predominant form of the drug present in plasma within 5 minutes of thiotepa administration The parent compound has a plasma half-life of 1.2 to 2 hours,... prolonged in the presence of hepatic or renal disease Almost one-half of the compound is excreted intact in the urine by tubular secretion Elevated urinary concentrations of 5aminoimidazole-4-carboxamide (AIC) are derived from the catabolism of dacarbazine, rather than by inhibition of de novo purine biosynthesis Concentrations of dacarbazine in CSF are approximately 14% of those in plasma (Friedman, . describing various types of agents. Figure IX 1. Summary of the Mechanisms and Sites of Action of Chemotherapeutic Agents Useful in Neoplastic Disease. PALA =N- phosphonoacetyl-L-aspartate; TMP =. cross-linkage, and DNA breakdown occurs. Specific repair enzymes for removing alkyl groups from the O-6 of guanine (guanine O 6 -alkyl transferase) and the N-3 of adenine and N-7 of guanine (3-methyladenine-DNA. differences in antitumor spectrum of the two agents. Although initially considered an antimetabolite, the triazene derivative 5-( 3,3-dimethyl-1-triazeno )- imidazole-4-carboxamide, usually referred