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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 855

4-Hydroperoxycyclophosphamide, a chemically stable form of the DNA cross-link and is poorly recognized by DNA repair processes,
reactive intermediate of cyclophosphamide, 4-hydroxycyclophospha- leading to marked cytotoxic potency of this cross-link.
mide, is more toxic to committed hematopoietic progenitors such as The pharmacokinetics of the chloroethyl nitrosoureas reveal a very
colony-forming unit–granulocyte/macrophages (CFU-GM), burst- short half-life. BCNU is predominantly used for high-dose treatment
forming unit–erythroids (BFU-E), and colony-forming unit–ery- of recurrent lymphomas. Regimens including BCNU induce sus-
throids (CFU-E). tained complete remission (CR) rates of approximately 40%–60%.
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Melphalan, or phenylalanine mustard, has an amino acid side Doses of between 300 and 600 mg/m have been safely administered.
chain that alters its cellular uptake and stabilizes its structure, allow- The chloroethyl nitrosoureas cause profound and cumulative BM
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ing PO administration (see Fig. 57.3). It is available in both PO and suppression at conventional doses of 120–150 mg/m , limiting treat-
IV forms, and has a similar effect on DNA cross-linking as cyclo- ment to three to five cycles at 6-week intervals.
phosphamide and the other nitrogen mustards. Melphalan uptake by Complications of high-dose BCNU therapy include pulmonary
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cells is by means of a neutral amino acid transporter. Its rate of toxicity and renal toxicity at doses higher than 600 mg/m . Pulmo-
cross-link formation is much slower than that of mechlorethamine, nary toxicity, as evidenced by a decrease in the DL CO (diffusing
presumably because of delayed metabolism. Oral melphalan is used capacity of the lung for carbon monoxide), occurs in up to 40% of
predominantly for the standard treatment of multiple myeloma patients. It can be managed with high-dose oral steroids during the
(MM) and IV in high-dose regimens in preparation for stem cell inflammatory phase. Interstitial nephritis with glomerulosclerosis,
transplantation (see Chapter 86) for MM patients. interstitial fibrosis, and dropout of tubules has been reported with
Chlorambucil has been used for more than 40 years for the treat- BCNU or CCNU.
ment of CLL. Chlorambucil is the phenylbutyric acid derivative of
nitrogen mustard and is very stable, entering the cell by diffusion
rather than by a specific uptake mechanism. It is typically adminis- Methylating Agents
tered orally on a daily basis or intermittently. It appears to have
greater bioavailability than melphalan and a more consistent half-life Four methylating alkylating agents are in clinical use. These include
of approximately 2 hours. procarbazine, DTIC, streptozotocin, and temozolomide. Procarba-
Busulfan is an alkylsulfonate unique among alkylating agents zine and DTIC are triazines. Streptozotocin is a monofunctional
because of two sulfur groups and lack of a chloroethyl moiety methyl nitrosourea derivative with an attached sugar moiety, and
(see Fig. 57.3). Busulfan, similar to the nitrogen mustards, reacts temozolomide is an imidazotetrazine. All react with DNA by under-
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predominantly at the N position of guanine and produces an going SN reactions forming a methyldiazonium ion, resulting in
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N –N biguanyl DNA cross-link, although the precise nature of methylation of N guanine (67%), O guanine (9%), O and O
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this cross-link appears different than that of the nitrogen mustards. thymine (2%), and N adenine (3%). None form DNA cross-links.
The pharmacokinetics of busulfan is important for its use in However, all induce high levels of DNA methylation, and their rec-
high-dose therapy for ablation of the BM in patients undergoing ognition and repair results in both single- and double-strand breaks.
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autologous transplantation for acute leukemia or allogeneic stem cell N methylguanine is removed through the BER system. Recognition
transplantation (see Chapter 104). Because the incidence of venooc- by the N-methylpurine glycosylase results in removal of the adducted
clusive disease is lower in patients receiving high-dose busulfan with base with formation of an abasic site that is recognized by the apurinic
predosing pharmacokinetics performed, this is now recommended in (AP) endonuclease, which then cleaves the backbone at the AP site.
high-dose regimens, the target being an area under the curve (AUC) Subsequently, the free 5′ sugar is released by DNA lyase, with repair
of 1125 µmol/L × min (range 900–1350) with every 6 hour dosing. initiated by β-polymerase and DNA ligase. BER effectively removes
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Busulfan is a potent stem cell toxin, killing both early and late hemato- N methylguanine and N methyladenine, and restores DNA to
poietic progenitor cells and damaging the BM stroma. Other toxicities normal. Inhibition of BER by the investigational agent methoxy-
of busulfan include nausea and vomiting, and pulmonary interstitial and amine (TRC102) blocks this pathway and increases toxicity.
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intraalveolar edema leading to fibrosis. The pulmonary fibrosis is distinct O methylguanine mispairs with thymine during DNA synthesis,
from the interstitial pneumonitis, which accompanies allogeneic stem resulting in a lesion recognized by the MMR system. Mispair recogni-
cell transplantation and is not related to cytomegalovirus or other viral tion proteins are MSH6, MSH3, and MSH2. Recognition of the
infections. mispair recruits additional proteins to the complex, including MLH1
and PMS1/PMS2. These proteins initiate exonuclease cleavage of a
long patch in the newly synthesized strand of DNA. This is then
Nitrosoureas repaired by polymerases-δ and -ε. If unrepaired, a thymine is repeat-
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edly inserted opposite the O methylguanine, resulting in multiple
Four chloroethyl nitrosoureas and one methyl nitrosourea are in single-strand breaks. Cells expressing high levels of the DNA repair
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clinical use. These agents are different from the nitrogen mustards in protein for O methylguanine, O methylguanine-DNA methyltrans-
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that they alkylate through an SN reaction, forming a highly reactive ferase (MGMT), are approximately 10-fold more resistant to meth-
intermediate in the presence of N, O, and P nucleophiles in DNA. ylating agents than MGMT-negative cells. Cells lacking MMR are
The commonly used clinical agent is (2-chloroethyl)-N-nitrosourea very resistant to methylating agents. Acquisition of MMR defects is
(BCNU). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-N-(2- associated with acquired resistance to methylating agents and cispla-
chloroethyl)-N-nitrosourea (ACNU) is commonly used in Japan. A tin, which is also recognized by this protein complex.
third agent, N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea (CCNU), Procarbazine was synthesized as a monoamine oxidase inhibitor
is used predominantly as an PO nitrosourea in children with brain and has been used since the 1950s for the treatment of Hodgkin
tumors. All of these compounds have high hydrophobicity, actively lymphoma and NHL, as well as a component of combination thera-
penetrating the blood–brain barrier. pies for gliomas. DTIC is metabolically activated by cytochrome
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The DNA alkylation sites include N and O of guanine. Chlo- P450 microsomal oxidoreductases, ultimately leading to formation
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roethylation at the O position of guanine appears critical to cyto- of the methyldiazonium ion and DNA methylation. DTIC is used
toxicity. DNA cross-linking by chloroethyl nitrosoureas include at in combination with ABVD for treating Hodgkin lymphoma (see
1-(3-cytosinyl), 2-(1-guanyl) ethane, and 1-2-bis(7-guanyl) ethane. Chapter 75) and is also used for patients with metastatic malignant
The former is responsible for much of the cytotoxicity observed with melanoma in combination with BCNU, cisplatin, and tamoxifen.
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the chloroethyl nitrosoureas. It is formed after alkylation at the O Activation of DTIC requires hydroxylation of one terminal methyl
position of guanine. This adduct undergoes intramolecular rearrange- group caused by demethylation forming 5-[3-methyl-triazen-1-yl]-
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ment to a circular intermediate, N . O ethanoguanine is formed, imidazole-4-carboxamide (MTIC), with spontaneous decomposition
which can then rearrange by attack at the opposite hydrogen-bonded to the methyldiazonium ion, which alkylates the DNA, as noted
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base N of cystine, forming the interstrand cross-link. This is a unique earlier. Maximum tolerated doses of DTIC are approximately