Pediatric chemotherapy has progressed from providing palliative and adjunctive therapy to providing either definitive primary therapy or one of the essential arms of multimodal therapy. Clinical studies have suggested that as many as 50 per cent of children with acute lymphoblastic leukemia may be cured of their disease,1 while most of the remaining affected children will have a significantly prolonged survival time. With surgery and radiation therapy alone, only 40 per cent of children with Wilms's tumor are cured, but with the addition of vincristine and dactinomycin, 80 per cent or more of these children will survive.2
Preceding and sometimes paralleling the advances made in clinical chemotherapy are the advances in knowledge concerning the factors that help direct rational therapy.3"5 These factors include normal and malignant cell kinetics, pharmacokinetics, the mechanism of action of various agents, and the biologic behavior of both experimental and human tumors. The chemotherapist of today must have a good general background in these aspects of cancer biology in order to plan and administer the most effective chemotherapeutic regimen for his patient.
FACTORS INFLUENCING RESPONSETOTHERAPY
There are many factors that influence the outcome of any therapeutic regimen. The single most important factor that determines survival is the extent of disease at the time of diagnosis. If the tumor is localized, surgery and/or radiation therapy can probably eradicate it. Chemotherapy, when used preoperatively, also has a role, since it may reduce an inoperable tumor mass to an operable size. Similarly, chemotherapy given before radiation therapy may decrease the size of the required radiation port, minimizing damage to surrounding tissue . Chemotherapy may also increase the therapeutic efficacy of radiation by enhancing radiation damage to malignant cells. Finally, if the tumor is widely disseminated or has a propensity to metastasize and occult metastasis may be present, chemotherapy may be able to eradicate disseminated tumor, resulting in the eventual cure of the host.
The pharmacokinetics of an antitumor agent depends on the physiologic status of the host, the anatomic location and biologic characteristics of the tumor, and the pharmacologie characteristics of the agent.3"5 Some of these factors are outlined in Table 1.
The physiologic status of the patient at the time therapy is to be initiated is important, because any significant alteration from normal can greatly influence drug metabolism. For example, if there is evidence of hepatic disease and a standard dose of adriamycin is administered, inordinately high tissue levels will occur because adriamycin is excreted primarily by the liver. Such factors as the route of administration, absorption, drug activation, detoxification, excretion, and diffusion must all be considered. Even when the drug reaches the target cells, there are many factors at the cellular level that will determine the ultimate effectiveness of chemotherapy. The cellular-level factors affecting chemotherapy include cell membrane permeability, quantity of target molecules, and repair of sublethal damage.
Another factor that affects chemotherapy is the proliferative state of the tumor. Almost all cells, normal as well as malignant, are sensitive to chemotherapeutic agents only when they are in a proliferative state. In addition, many agents exert their lethal effect only when cells are going through the DNA-synthetic (S) phase of the cell cycle. Even in the growing child most cells are not proliferating, and there are generally only three normal proliferative tissues that are affected by chemotherapeutic agents; hematopoietic stem cells of bone marrow, stem cells of the gastrointestinal mucosa, and stem cells of hair follicles. Generally the agents also produce immunosuppression, presumably as a result of damage of the lymphatic tissue. Toxicity to all these tissues is reversible providing the patient does not die of intercurrent complications , It is not surprising, therefore, that drug therapy is usually limited by the toxicity accrued by the bone marrow and gastrointestinal tract.
Some of the agents used appear to damage nonproliferating, metabolically active cells, but this damage does not seem to be irreversible unless the cell is undergoing DNA synthesis. LAsparaginase may thus cause profound disturbance in liver function, but evidence of damage rapidly disappears once L-asparaginase therapy is stopped.
FACTORS THAT DETERMINE THE EFFECTIVENESS OF THERAPY
Figure 1. Theoretical compartments of the normal bone marrow.
Figure 2. Theoretical compartments of a tumor.
NORMAL AND MALIGNANTCELL COMPARTMENTS
Schematic diagrams of normal tissue (bone marrow) and a malignant tumor (Figures 1 and 2 respectively) should provide a better understanding of the effects of chemotherapeutic agents on proliferative tissue. In Figure 1 the stem cell compartment is small, since these cells probably constitute less than 2 per cent of the normal cells in the bone marrow. Only a few cells of the stem cell compartment are actively proliferating. Some of these stem cells contribute progeny to the proliferating compartment; others divide to maintain a constant cell number in the stem cell compartment. (A cell that is not proliferating but can resume proliferation is said to be in a G0 phase, and the stem cell compartment could thus be called a G0 compartment.) Once the stem cells enter the proliferative compartment, most begin to differentiate into recognizable myeloid, erythroid, and monocytic cells, and re-entry into the stem cell compartment is probably impossible. From here cells pass into the maturational compartment, where they no longer divide but develop their normal mature morphology and are then extruded into the bloodstream.
The compartments of a theoretical tumor are illustrated in Figure 2. In this tumor, cells are entering the proliferative compartment from a nonproliferating G0 compartment. These tumor cells are capable of indefinite proliferation, presumably because oí a loss of feedback control of stem cell proliferation. Some proliferating cells may re-enter the G0 compartment. Because tumors tend to outgrow their blood supply, some of the proliferating cells may also stop dividing as a result of inadequate nutrients or oxygen. This is the poorly vascularized compartment in Figure 2. Some cells may go on to cell death (dead cell compartment), but others may re-enter the proliferative compartment if the vascular supply improves. In some tumors differentiation occurs, but these cells are probably not capable of indefinite proliferation and thus do not constitute a danger to the patient. Most childhood tumors seem to have little differentiated tissue; ganglioneuroblastoma isa notable exception. Some of these differentiated cells may ultimately die and enter the dead cell compartment. Unfortunately, at any time during their development, tumor cells may enter the bloodstream or lymphatics and metastasize to distant tissue. The metastatic sites could then send malignant cells back to the primary tumor.
It is important to be aware of these compartments, since response to therapy will depend on the relative size of these compartments and the transit of tumor cells from one compartment to another. Cells in the G0 state are especially resistant to chemotherapeutic agents, since their response to cytotoxic agents closely resembles that of the normal stem cells of the body. If there is inadequate perfusion of a portion of the tumor, there will be inadequate drug concentration in that compartment and effective cytotoxic levels will not be achieved. Also, cells that are placed in a nutritionally deficient state probably will not initiate DNA synthesis but will remain in a preDNA-synthetic (Gi) phase or perhaps a post-DNA-synthetic (G2) phase. Presumably, as cells of the actively proliferating fraction are destroyed, cells in the G0 compartment provide proliferating cells to take their place. Another source of proliferating cells is the hypoxic and nutritionally deficient compartment, which may begin to receive nutrients4 or oxygen and begin to proliferate. Chemotherapy must be continued if these cells entering active cell proliferation are to be killed.
CLASSIFICATION OF AGENTS
Chemotherapeutic agents have been classified according to their effects on cells in these various compartments.6 Studies have been done on the normal hematopoietic stem cell compartment, which contains cells primarily in the G0 state, and on the proliferating cells of a transplanted leukemia. Two distinct patterns of cell kill are observed (Figures 3 and 4). In Figure 3 the effect of increasing doses of an S-phasespecific agent administered over a fourhour period is examined. In both cell lines an exponential drop in cell survival is noted, followed by a plateau level, after which increasing doses of the agent do not result in increased cell kill. Since only a few of the hematopoieuc stem cells are proliferating at any given time and even fewer are going through S phase, the lethal effect on that compartment is minor. All the malignant cells are proliferating, however, and the reduction in the number of malignant cells greatly exceeds that of the hematopoietic stem cells.
Figure 3. Effect of phase-specific agents on normal and malignant cells. Phase-specific agents kill cells only during a specitlc sensitive phase of the cell cycle. Nonproliferatlng (Go) cells are illustrated as opaque circles (*). Proliferating cells are illustrated as open circles (O or *). Sensitive cells are illustrated as open circles with a central dot *). Cells that are sensitive to the lethal action of the agent are crossed out (⊗).
A chemotherapeutic agent that kills proliferating cells regardless of the phase of the cell cycle results in exponential cell kill with increasing doses of the drug (Figure 4); both hematopoietic stem cells and leukemic cells are killed. But since most of the hematopoietic stem cells are not proliferating, their sensitivity to the agent is much less than that of proliferating cells that are all in cycle.
Figure 4. EfIoCt of cycle non-phase-specific agents on normal and malignan! cells. Cycte-speciiic agents will preferentially kill all cells in cycle, regardless of the phase of the cell cycle. Nor proliferating (GQ) cells are illustrated as opaque circles (·). Proliferating cells are illustrated as open circles (O or @). Cells that are sensitive to the lethal action of the agent are crossed out (8+ ).
These observations strongly suggest that phase-specific agents should be administered in multiple doses and the therapeutic regimen designed so the drug can be given frequently, with toxicity maintained at a subclinical level. A cycle-specific agent should be administered at infrequent intervals. Thus, a single maximum-tolerated dose can be given and not repeated until the patient has recovered from the toxic effects of the drug.
It is impossible to discuss here all the chemotherapeutic agents that have been used clinically. Instead, only the drugs with proven effectiveness or new drugs that look promising in the treatment of pediatrie malignancies are mentioned. A description of their biochemical structures and mechanisms of action is given, if known, along with a discussion of their significant toxicities. For further information the reader should seek more extensive reviews. s'7'8
Table 2 lists drug preparations and their storage requirements, stability, routes of administration, and principal toxicities. Table 3, a parallel list, cites the tumors against which the agents have been shown to have significant antitumor activity. A blank does not necessarily mean that the drug is ineffective, only that sufficient clinical trials are not available to establish the degree of effectiveness. Although some studies may indicate that antitumor activity is minimal, negative ratings are deliberately not included, since future trials may prove that the agent is effective in combination therapy.
The evidence accumulating from clinical trials on combination chemotherapy overwhelmingly suggests that this method is preferable to the use of single agents. Which agents should be given simultaneously and which should be used sequentially have been determined in a somewhat empirical fashion. But there are some guidelines that have been followed. Attempts have been made to select the chemotherapeutic agents that have widely divergent toxicities so that the maximum tolerated dose of each drug can be administered. Thus, in general, two severely myelotoxic agents are not given simultaneously. In order to obtain maximum cell kill, some studies have attempted to administer a cycle-specific agent with a phase-specific agent. Other studies have tried to synchronize cells so that the replicating cells proceed through cell cycle in unison, with one agent followed at a critical interval by another agent. Much more knowledge is needed about the pharmacologie activities of the drug, as well as about the biologic and biochemical behavior of the tumor cells, before a truly intelligent decision on combination therapy can be reached.
No attempt has been made to list the maximum-tolerated dose of each drug or to detail any of the therapeutic regimens. Since most of the drugs are given in combination, the tolerated dose of a specific drug depends on the dose and schedule of the agents administered and the physiologic status of the patient. The selection of a therapeutic regimen depends on the type of tumor and the location and extent of disease.
Methotrexate (MTX, amethopterin) binds irreversibly to dihydrofolate reductase, preventing the conversion of folie acid to tetrahydrofolate and thus interfering with pyrimidine synthesis.' This effect can be reversed by folinic acid or thymidine,10 a factor that has been very helpful in the design of various therapeutic regimens. Thus, methotrexate can be given intrathecally even in the presence of severe systemic toxicity of the drug, with further toxicity prevented by the systemic administration of folinic acid. Similarly, high doses of methotrexate can be given by regional intra-arterial perfusion and the systemic effects blocked by folinic acid. Very high doses of methotrexate -100-200 mg./kg. or more- have been administered in patients with osteosarcoma and further systemic toxic effects blocked three to six hours later by folinic acid.11
The principal toxic side effects of methotrexate administered systemicalIy are mucosal ulcération and bone marrow depression. Three relatively uncommon but serious complications are (1) toxic hepatitis leading to hepatic fibrosis,12 (2) a peculiar disturbance in bone metabolism with severe osteoporosis,13 and (3) pneumonitis.14 The signs and symptoms of toxic hepatitis and osteoporosis regress once therapy is stopped, but hepatic fibrosis is irreversible. Thus, a patient receiving long-term maintenance therapy should have periodic liver function studies to guard against irreversible fibrosis. Although pneumonitis associated with methotrexate administration has been found to be of infectious origin in many instances, histopathologic examination on other occasions has revealed an allergic-type inflammatory response without a demonstrable pathogen. In addition, the signs and symptoms of pneumonitis have disappeared in some patients despite the continued administration of methotrexate. Another toxicity, which is seen only with massive doses of methotrexate, is toxic nephropathy.15 This toxicity is also reversible. Methotrexate is excreted primarily through the kidneys, and methotrexate toxicity can be markedly enhanced if there is only minor subclinical renal damage. Thus, methotrexate therapy should be given cautiously when there is a history of renal disease, even if routine renal function studies are normal.
Methotrexate given intrathecally is associated with many signs and symptoms of toxicity, including pain at the site of local intrathecal injection, meningismus with fever and headache, transient or permanent hemiparesis, and convulsions, dementia, and death. About 10 per cent of the children receiving intrathecal methotrexate for overt central nervous system disease have some evidence of toxicity. This toxicity is manifested by nausea, vomiting, headache, meningismus, pleocytosis, elevation of CSF protein, and/ or decrease in flow of cerebral spinal fluid on repeat lumbar puncture. In children receiving intrathecal methotrexate maintenance therapy, almost 40 per cent show evidence of toxicity.16 The incidence of these symptoms has decreased with concomitant administration of intrathecal hydrocortisone.
6-Mercaptopurine (6-MP), an analogue of xanthine, must be converted to its ribonucleotide before it interferes with purine biosynthesis.17 6-MP is detoxified by the action of xanthine oxidase to 6-thiouric acid. If allopurinol, a xanthine oxidase inhibitor, is administered at the same time, toxicity is enhanced because 6-MP is not detoxified as rapidly. It is suggested that, if allopurinol is to be administered with 6-MP, the dose of 6-MP be reduced to 25 per cent of the estimated dose.
The toxicity of 6-mercaptopurine is due primarily to myelosuppression, although oral ulcérations rarely occur. A characteristic but unusual complication of 6-MP toxicity is lower abdominal pain, which is relieved by defecation. Toxic dermatitis has been observed with 6-MP, but this is rarely severe. Toxic hepatitis is an extremely rare complication.
6-Thioguanine was thought, initially, to exert its lethal effect by interfering with purine biosynthesis, but further studies have shown that it is incorporated into DNA, inhibiting further synthesis.18 The principal toxicity of 6-thioguanine is bone marrow depression. Most clinical studies that have been reported utilized 6-thioguanine as an oral preparation, but oral absorption can be erratic.
Arabinosyl cytosine (ara-C, cytosine arabinoside, cytarabine, and Cytosar®), an analogue of deoxycytidine, must first be metabolized to its active compound, ara-C triphosphate. The compound inhibits RNA, protein, and especially DNA synthesis by directly inhibiting DNA polymerase.19 It is detoxified by converting arabinosyl cytosine to arabinosyl uracil, an inactive catabolite. Ara-C and the inactive catabolites are excreted. Clinical20 and preclinical21 studies indicate that either frequent divided doses or continuous intravenous infusions of ara-C provide optimal therapy. The dose-limiting toxicity is myelosuppression. With rapid intravenous infusion, nausea and vomiting may occur. Toxicity due to intrathecal ara-C therapy is similar to the complications observed with intrathecal methotrexate therapy.
5-Fluorouracil (5-FU), a fluorinated analogue of uracil, is incorporated into RNA and interferes with the enzyme thymidylate synthetase and, thus, with the synthesis of DNA. " The single-dose-limiting toxicity is nausea and vomiting; the multiple-dose-limiting toxicity is diarrhea and myelosuppression. Initially the drug was given on a daily schedule, but a weekly or twice-weekly schedule is equally effective and less toxic. Furthermore, the intravenous preparation can be given orally at the same dose level with equal effectiveness. Therapy should be administered carefully in the presence of hepatic damage because this drug is excreted primarily by the liver.
Imidazole carboxamide (dimethyl triazeno-imidazole carboxamide, DIC), an analogue of amino-imidazole carboxamide, is an experimental agent that has shown significant antitumor activity, especially in combination with other agents. It is light-sensitive and must be stored at -4° C. Its mechanism of cell kill is uncertain. DIG has been shown to interfere with synthesis of RNA, protein, and, especially, DNA. There is some recent evidence that it alkylates DNA.23 Myelosuppression is the dose-limiting toxicity. Nausea and vomiting may be observed, but this factor is usually significant only on the first day. An infrequent flulike syndrome with myalgia is observed.
Alkylation is the replacement of a hydrogen atom of a molecule by an alkyl group. The lethal effect of alkylating agents is due to their irreversible biochemical combination with nucleophilic substances.24 The target sites are generally amines, phosphates, and carboxyl and sulfhydryl groups. Although the alkylating agents can, and do, alkylate small-molecularweight substances, their main lethal effect seems to be due to the alkylation of nucleotide chains, particularly DNA.
Nitrogen mustard (Mustargen®), one of the first chemotherapeutic agents to be used clinically, was developed as a result of a study on poisonous war gases. It must be given in a free-flowing intravenous infusion. Extreme care should be taken to avoid extravasation into local tissue, since ulcération will result. Precaution also must be taken in the mixing and administration of this drug. Eyeglasses or goggles should be worn while the drug is mixed, and if there is any contamination of the skin, the area should be rinsed immediately with copious amounts of water. Nausea and vomiting can usually be controlled if the drug is given to the patient just before he retires in the evening, and if antiemetics are administered. Diarrhea may also be a problem. Myelosuppression is the dose-limiting toxicity of nitrogen mustard therapy. The nadir of bone marrow depression may not occur for two to three weeks after administration; as a result, this drug is usually administered at intervals of three to four weeks.
Cyclophosphamide (Cytoxan® ) is a cyclic nitrogen mustard. It is biochemically inert until metabolized by the liver into a number of cytotoxic compounds." Although initially it was thought that the antitumor effect of cyclophosphamide would closely resemble the parent compound, nitrogen mustard, experimental and clinical studies have clearly indicated a much broader range of activity.26 The principal lethal metabolites of cyclophosphamide have not yet been determined. Since it is inert, it can be given via any route without local side effects.
Myelosuppression occurs, but the duration of impaired hematopoiesis is usually short. Cyclophosphamide is known as a platelet-sparing compound because platelet counts are usually not significantly depressed. The active compound is excreted, unchanged, through the kidneys, reaching very high concentrations in the bladder. Unless some prophylactic measures are taken, a toxic hemorrhagic cystitis will develop. In order to prevent this complication, cyclophosphamide should be given in the morning and the child urged to take 3,000 ml./sq.m. or more of fluids daily. The parent should be warned to watch for any signs and symptoms of dysuria and to check the urine daily for gross hematuria. If an episode of hematuria should develop, therapy must be stopped until the urinalysis returns to normal.
In order to prevent the recurrence of hemorrhagic cystitis, it is recommended that the parents arouse the child at approximately 2 or 3 A.M. so he can empty his bladder. If the hematuria should recur or persist for an unusually long time, a voiding cystogram should be obtained to check for bladder contraction. If bladder contraction is present, cyclophosphamide administration must be stopped and not resumed until evidence of contraction has disappeared. Cyclophosphamide therapy should not be given simultaneously with radiation therapy to the pelvic region. Amenorrhea and aspermia have been noted in adults receiving cyclophosphamide, and may also prove to be a problem for children given this drug who survive to adulthood.
Chlorambucil (Leukeran®) is an oral nitrogen mustard compound. It is given on a daily schedule, and the dose-limiting toxicity, myelosuppression, is rarely severe. Nausea and vomiting are also rarely seen with a standard regimen. Dermatitis and hepatotoxicity are observed very rarely.
Phenylalanine mustard (Alkeran®, melphalan, L-PAM, L-sarcolysin) is a nitrogen mustard that can be given orally or intravenously . The main dose-limiting toxicity is myelosuppression. Nausea and vomiting do occur but are usually not severe.
Busulfan (Myleran®), a sulfonic acid mustard, is administered on a daily schedule. The principal toxicity is myelosuppression, which, on rare occasions, is irreversible. Endocrinelike disturbances and pulmonary fibrosis have been observed in patients receiving long-term therapy.
BCNU(bis[chloroethyl]nitrosourea), an N-alkyl-N nitrosourea, is fairly unusual in that it is lipid-soluble and will pass the "blood-brain barrier" in adequate concentrations to treat central nervous system malignancies. There are a number of problems with administration of this drug. H must be brought into solution with ethyl alcohol and then diluted with 5 per cent glucose and water. When the drug is given intravenously, the patient may complain of pain at the site of injection; thus it is better to administer the drug by infusion. Myelosuppression, the dose-limiting toxicity of the drug, is greatly delayed and may not occur until four to six weeks after administration. Thus, repeated doses must be given with extreme caution. Other complications are phlebitis of the vein along the route of administration and local ulcération if there is extravasation. Nausea, vomiting, and diarrhea are also observed. Hepatic toxicity is rare.
Actinomycin D (dactinomycin, Cosmegen®) is a light-sensitive yellow crystalline antibiotic prepared from Streptomyces. This drug intercalates with the minor groove of the DNA helix and interferes with RNA transcription.27 Nausea and vomiting are frequently associated with administration of this drug, but its dose-limiting toxicities are diarrhea and myelosuppression. The drug enhances the lethal effects of irradiation, and some reduction of x-ray dose may be required to prevent intolerable toxicity to irradiated tissues. Alopecia is a frequent and undesirable side effect. Ulcération will result if there is extravasation of the compound. If radiation therapy is given to the mucous membranes in association with actinomycin D therapy, the resultant stomatitis and mucosal ulcération will also be greatly enhanced. Because the drug is excreted primarily by the liver, great care must be taken if there is any evidence of liver damage.
Adriamycin (hydroxyl daunorubicin) is an anthracycline antibiotic prepared from Streptomyces peucettus. This drug intercalates with the major groove of DNA, Z8 preventing transcription of RNA and replication of DNA. It is similar to actinomycin D in that the lethal level persists in the body for a prolonged period.29
The principal toxicities are myelosuppression after short-term therapy and cardiomyopathy after long-term therapy. The total administered dose should not exceed 600-700 mg./sq.m., and if the patient has received radiation therapy to the heart, the dose should probably not exceed 500 mg./ sq.m. The nadir of myelosuppression after a short intensive course of adriamycin occurs in about 10 to 12 days and may be associated with fever and stomatitis. Since sepsis complicated by myelosuppression also occurs then, it may be necessary to treat with antibiotics. Recovery from myelosuppression is usually rapid and complete within three weeks of administration. Nausea and vomiting may occur, and alopecia is a frequent complication. The parents should be alerted that a reddish discoloration of the urine will occur after administration and is not a cause for concern. The compound is excreted primarily by the liver, and the dosage must be appropriately reduced in the presence of hepatic damage.
Daunorubicin (daunomycin, rubidomycin) differs from adriamycin only in the absence of a hydroxyl group. It is derived from the same bacterial organism as adriamycin and has almost the same antitumor spectrum and toxicities.30 In children, adriamycin seems to be a superior compound to daunorubicin.
Bleomycin (Blenoxane®), isolated from a strain of Streptomyces verticilius, probably exerts its lethal effect by binding to DNA, causing strand scission.31 The principal distribution of an administered dose of bleomycin is to the lungs and skin. This undoubtedly relates to its most serious side effect, pulmonary fibrosis, which may be fatal. Low-grade fever, fatigue, and hypertropic skin changes also occur. Myelosuppression has not been reported.
Vincristine (Oncovin®) and vinblastine (Velban®), plant alkaloids derived from the periwinkle plant, Vinca rosea, have widely different clinical applications" (Table 3), although they differ structurally only by a single oxygen atom. Both compounds cause peripheral neuropathy, but vincristine is much more toxic than vinblastine in this respect. Within a day or so after administration of vincristine, the patient may suffer severe jaw pain that may represent peripheral paresthesia. It is interesting that this problem decreases with each subsequent dose of vincristine and generally disappears by the third or fourth dose. Obstipation is a very serious complication; if it is present, subsequent doses of vincristine should be delayed until normal bowel patterns are established. If obstipation is unusually severe, subsequent doses should be decreased. Peripheral neuropathy is manifested by foot drop or an inability to pick up small objects and requires either cessation of therapy or a marked delay and subsequent decrease in dosage. Most of these patients develop hypotonie reflexes, but this should not be an indication for alteration of therapy. Another disturbing noxious side effect is the mental depression that these patients suffer. Vinblastine can also cause these toxicities, but bone marrow suppression is much more common and is usually the doselimiting toxicity. Both compounds cause local ulcération if there is extravasation, and both are associated with alopecia. Since they are excreted by the liver, therapy must be administered cautiously in the presence of hepatic damage.
ANTITUMOR ACTIVITY OF CHEMOTHERAPEUTlC AGENTS FOR VARIOUS PEDIATRlC MALIGNANCIES
L-Asparaginase, an experimental agent, exerts its lethal effect by causing an acute asparagin deficiency in the plasma by metabolizing asparagin to aspartic acid and ammonia.33 In tumor cells that cannot metabolize asparagin, protein synthesis is impaired and there is some inhibition of the synthesis of RNA and DNA. Although asparagin is not usually considered an essential amino acid, normal cells will show signs of asparagin insufficiency. This probably accounts for some of the toxic side effects that are observed.
The principal toxic side effect is related not to the mode of action by the drug but, rather, to hypersensitivity reactions secondary to impurities of the enzyme preparation. A patient with hypersensitivity reactions to Lasparaginase derived from Escherichia coli can be treated safely with L-asparaginase from Erwinia carotovora. The hypersensitivity reactions vary from a mild transient erythematous rash to anaphylaxis and death.34 It is stated that the hypersensitivity reactions can be greatly decreased by administering the drug intramuscularly rather than intravenously. Other severe reactions that may be due to hypersensitivity and/or asparagin-induced deficiency are moderately severe disturbances in liver function studies, as manifested by low plasma albumin and low clotting factor levels, and pancreatic toxicity, with an occasional death due to pancreatic insufficiency. Despite the fact that laboratory evidence of liver damage may be impressive, clinical symptoms from disturbance of liver function are rare. Jaundice has been observed, but this clears despite continued administration of the drug. Fever, anorexia, nausea, and vomiting are minor toxicities.
Procarbazine (methylhydrazine, MIH, Natulan, Matulane®) is a weak monamine oxidase inhibitor. Its exact cytotoxic effects are unknown,35 but it has been shown to inhibit the synthesis of protein, RNA, and DNA and to alkylate DNA. The compound is unstable in water. The chief dose-limiting toxicity is myelosuppression, although nausea and vomiting may also be doselimiting. Since it is a monamine oxidase inhibitor, it should not be administered with other monamine oxidase inhibitors, with sympathomimetic drugs, or with tricyclic antidepressants. The patient should avoid alcohol and foods with high tyramine content, such as ripe bananas or aged cheese. Procarbazine may further potentiate the effects of barbiturates, phenothiazines, antihistamines, narcotics, and hypotensive
agents. The patient may become depressed and drowsy, and parasthesia, neuropathies, or hyperexcitability may occasionally be observed. Dermatitis may occur.
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FACTORS THAT DETERMINE THE EFFECTIVENESS OF THERAPY
ANTITUMOR ACTIVITY OF CHEMOTHERAPEUTlC AGENTS FOR VARIOUS PEDIATRlC MALIGNANCIES