Human Developmental Toxicants - Part 2 pptx

The drug is commercially available as Leukeran®and has a pregnancy risk factor of D labeling states “can cause fetal harm when administered to a pregnant woman: it is probably teratogeni

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5 Chlorambucil

Chemical name: 4-[Bis(2-chloroethyl)amino]benzene butanoic acid

Alternate name: Chloraminophene

CAS #: 305-03-3SMILES: c1(ccc(cc1)CCCC(O)=O)N(CCCl)CCCl

INTRODUCTION

Chlorambucil is an alkylating antineoplastic agent used therapeutically in the management ofchronic lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma and several other malig-nancies It is a derivative of mechlorethamine, another human developmental toxicant As withother alkylators, chlorambucil interferes with DNA replication and RNA transcription by alkylationand cross-linking DNA strands (Lacy et al., 2004) The drug is commercially available as Leukeran®and has a pregnancy risk factor of D (labeling states “can cause fetal harm when administered to

a pregnant woman: it is probably teratogenic in humans”)

DEVELOPMENTAL TOXICOLOGY

A NIMALS

The drug has been tested in the laboratory for developmental toxicity in rodents As expected, thedrug is teratogenic in mice (Didcock et al., 1956) and rats (Murphy et al., 1958) when givenintraperitoneally either once or twice during organogenesis at doses ranging from 6 to 40 mg/kg/day.Digit, limb, and central nervous system defects and cleft palate were produced The drug is alsoembryolethal and causes stunting in rodents at doses in the range of 5 to 10 mg/kg by the sameroute (Murphy et al., 1958; Tanimura et al., 1965)

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24 Human Developmental Toxicants

this toxicity ranged from 4 to 24 mg/day orally, and treatments ranged from conception throughthe 20th week of gestation These levels are greater than the usual therapeutic doses of 2 to 4mg/day po There does not appear to be a syndrome of malformations other than for near-identicalmalformations of the urogenital system in two of the four cases Interestingly, similar if not identicaldefects were produced in rats treated with the drug (Monie, 1961) Case # 5 was a twin pregnancy,and the other infant was spared the defect The malformations were accompanied in five of the sixcases by infant death No intrauterine growth retardation was recorded, contrary to a review oftreatment with antineoplastic drug therapy in humans, including chlorambucil, which was said toresult in 40% of infants having low birth weight (Nicholson, 1968) There were no postnatalfunctional alterations reported in the single surviving infant Only four nonmalformed infants werereported after chlorambucil use (Baynes et al., 1968; Nicholson, 1968; Jacobs et al., 1981; Zuazu

et al., 1991); therefore, based on this published information, the risk to developmental toxicity ishigh, on the order of 60%

CHEMISTRY

Chlorambucil is an aniline mustard of near average size The compound is hydrophobic and of lowpolarity Chlorambucil can participate in hydrogen bonding The calculated physicochemical andtopological properties are as follows

P HYSICOCHEMICAL P ROPERTIES

TABLE 1 Developmental Toxicity Profile of Chlorambucil in Humans Case

Number Malformations

Growth Retardation Death

Functional Deficit Ref.

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Murphy, M L., Moro, A D., and Lacon, C (1958) Comparative effects of five polyfunctional alkylating agents on the rat fetus, with additional notes on the chick embryo Ann NY Acad Sci 68: 762–782 Nicholson, H O (1968) Cytotoxic drugs in pregnancy Review of reported cases J Obstet Gynaecol Br Commonw 75: 307–312.

Revol, L et al (1962) [Hodgkin’s disease, lymphosarcoma, reticulosarcoma and pregnancy] Nouv Rev Fr Hematol. 2: 311–325.

Rugh, R and Skaredoff, L (1965) Radiation and radiomimetic chlorambucil and the fetal retina Arch Ophthalmol 74: 382–393.

Shotton, D and Monie, I W (1963) Possible teratogenic effect of chlorambucil on a human fetus JAMA

Zuazu, J et al (1991) Pregnancy outcome in hematologic malignancies Cancer 67: 703–709.

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6 Mechlorethamine

Chemical name: 2-Chloro-N-(2-chloroethyl)-N-methylethanamineAlternate names: Nitrogen mustard, chlormethine

CAS #: 51-75-2SMILES: N(CCCl)(CCCl)C

INTRODUCTION

Mechlorethamine is an alkylating antineoplastic drug that has therapeutic utility in combinationtherapy for Hodgkin’s disease and non-Hodgkin’s lymphoma and other malignant lymphomas Thedrug inhibits DNA and RNA synthesis via formation of carbonium ions by cross-linking strands

of DNA, causing miscoding, breakage, and failure of replication While the drug is not cell-phasespecific, its effect is most pronounced in the S-phase, and cell proliferation is arrested in the G2phase (Lacy et al., 2004) The drug used commercially has the trade name Mustargen®, amongothers, and it has a pregnancy risk factor of D (labeling states “can cause fetal harm whenadministered to a pregnant woman”)

A NIMALS

Mechlorethamine is teratogenic in all laboratory species tested Parenteral routes of administrationwere used In the mouse, subcutaneous or intraperitoneal injection caused digit anomalies andhydrocephalus, as well as growth retardation and embryolethality (Danforth and Center, 1954;Thalhammer and Heller-Szollosy, 1955) In rats, mechlorethamine elicited multiple malformations,death, and growth retardation following subcutaneous administration (Haskin, 1948) Malforma-tions were also produced in rabbits after intravenous dosing early in gestation (Gottschewski, 1964)

In a seldom-used animal species, the ferret, malformations were induced in high incidence uponinjection of mechlorethamine (Beck et al., 1976) Developmental toxicity was produced in animals

at parenteral doses ranging from 1 μg/g/day in mice, 0.1 mg/kg/day in rabbits, 0.5 mg/kg/day inferrets, to 1 mg/kg/day in rats, in decreasing order of sensitivity

N Cl

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H UMANS

The drug has been associated with congenital malformation in the human as well Recorded inthe literature were at least eight cases from first trimester exposure as well as other developmentaltoxicity as shown in Table 1 The malformations recorded are diverse, having similarities in twocases with digit abnormalities and three with brain defects The digit defects were similar to somerecorded animal malformations Further, in most cases, mechlorethamine was accompanied bycombined antineoplastic drug treatment (especially procarbazine and vinblastine/vincristine asMOPP); thus, the teratogenic effect of this drug cannot be established with certainty Malformationswere accompanied by dysmaturity in one case and learning disability in a single case, neither ofwhich are considered significant biological effects in the developmental toxicity parameter of thisagent Death or abortion occurred in the majority of the cases and was considered an associatedfeature of the developmental toxicity profile of mechlorethamine Doses recorded in the cases,when stated, were 4 to 6 mg/m2 po, and all cases are believed to have been limited to treatment

in the first trimester Therapeutic doses of this drug are much lower, 0.4 mg/kg (single dose) or0.1 mg/kg (repeated doses) by the iv route, which are doses similar to the effect levels in animalstudies Based on the number of unaffected infants born after being exposed to mechlorethamineduring the first trimester (Nicholson, 1968; Jones and Weinerman, 1979; McKeen et al., 1979;Whitehead et al., 1983; Andrieu and Ochoa-Molina, 1983; Green et al., 1991; see Schardein, 2000),the risk of developmental toxicity from this agent appears to be on the order of 22% One group

of experts stated the magnitude of teratogenic risk for this drug to be small to moderate (Friedmanand Polifka, 2000)

For more information, see the review article by Dein et al (1984) on the developmental toxicity

of mechlorethamine and other antineoplastic drugs useful in treating Hodgkin’s disease

Growth Retardation Death

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Green, D M et al (1991) Congenital anomalies in children of patients who received chemotherapy for cancer

in childhood and adolescence N Engl J Med 325: 141–146.

Haskin, D (1948) Some effects of nitrogen mustard on the development of external body form in the fetal rat Anat Rec 102: 493–511.

Jones, R T and Weinerman, B H (1979) MOPP (nitrogen mustard, vincristine, procarbazine and prednisone) given during pregnancy Obstet Gynecol 54: 477

Lacy, C F et al (2004) Drug Information Handbook (Pocket) 2004–2005, Lexi-Comp, Inc., Hudson, OH McKeen, E A et al (1979) Pregnancy outcome in Hodgkin’s disease Lancet 2: 590

Mennuti, M T., Shepard, T H., and Mellman, W J (1975) Fetal renal malformation following treatment of Hodgkin’s disease during pregnancy Obstet Gynecol 46: 194–196.

Nicholson, H O (1968) Cytotoxic drugs in pregnancy Review of reported cases J Obstet Gynaecol Br Commonw 75: 307–312.

Revol, L et al (1962) [Hodgkin’s disease, lymphosarcoma, reticulosarcoma and pregnancy] Nouv Rev Fr Hematol 2: 311–325.

Schardein, J L (2000) Chemically Induced Birth Defects, Third ed., Marcel Dekker, New York, p 585 Thalhammer, O and Heller-Szollosy, E (1955) Exogene Bildungfehler (“Missbildungen”) durch Lostinjekion bei der graviden Maus (Ein Beitrag zur Pathogenese von Bildungsfehlern) Z Kinderheilk 76: 351 Thomas, L and Andes, W A (1982) Fetal anomaly associated with successful chemotherapy for Hodgkin’s disease during the first trimester of pregnancy Clin Res 30: 424A.

Thomas, P R M and Peckham, M J (1976) The investigation and management of Hodgkin’s disease in the pregnant patient Cancer 38: 1443–1451.

Whitehead, E et al (1983) The effect of combination chemotherapy on ovarian function in women treated for Hodgkin’s disease Cancer 52: 988–993.

Zemlickis, D et al (1993) Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.

Teratog Carcinog Mutag 13: 139–143.

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7 Cytarabine

Chemical name: 1-β-D-ArabinofuranosylcytosineAlternate names: Ara-C, cytosine arabinoside, aracytidine

CAS #: 147-94-4SMILES: C1(N2C(N=C(C=C2)N)=O)OC(C(C1O)O)CO

INTRODUCTION

Cytarabine is a purine antimetabolite used therapeutically as an antineoplastic agent, as it is active

in treating leukemia and lymphoma Its mechanism of action is by inhibition of DNA synthesis,through conversion to its active compound, aracytidine triphosphate, which is incorporated intoDNA, inhibiting DNA polymerase and resulting in decreased DNA synthesis and repair; it is rapidlymetabolized (Lacy et al., 2004) The drug is specific for the S phase of the cell cycle Commerciallyavailable as Cytosar®, it has a pregnancy risk factor of D (This category would indicate that thedrug can cause fetal harm when administered to a pregnant woman.)

A NIMALS

Among animalstudies, cytarabine is teratogenic, and it increased fetal mortality and inhibited fetalbody weight when given to mice during the organogenesis period of gestation (Puig et al., 1991).Cleft palate, renoureteral agenesis or hypoplasia, and poly- or oligodactyly in association withmaternal toxicity were observed at intraperitoneal (IP) dose levels of 2 and 8 mg/kg/day, andresorption and decreased fetal body weight were observed at the higher dose In an earlier study

in mice, researchers recorded microcephaly with microscopic central nervous system malformations

at a higher dose of 30 mg/kg/day ip (Kasubuchi et al., 1973) In another study, researchers observedthe full pattern of developmental toxicity at an intravenous dose of 1.5 mg/kg/day during organo-genesis in the same species (Nomura et al., 1969) In the rat, IP doses over a wide range (20 to

800 mg/kg/day) during 4 days of organogenesis produced cleft palate, limb, tail, and digit mations, and fetal death in the offspring (Chaube et al., 1968) Toxicity was also recorded in the

malfor-N O

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2-day-old neonatal rat at doses of 4 mg/kg for 5 days by the IP route (Gough et al., 1982) Thetoxicity was manifested by weight gain suppression, delayed hair growth, toxic clinical signs,cerebellar hypoplasia, retinal dysplasia, and delayed nephrogenesis

H UMANS

There are a few recorded cases of malformation in humans (Table 1) Of some 16 cases illustratingdevelopmental toxicity in humans with cytarabine (and usually combined antineoplastic therapy),

3 had malformations, all with digit defects, accompanied by large bone (leg) malformations in 2

of the cases Dosage was not specified except in one case, at 160 mg/day intravenously in the first

2 months of pregnancy Therapeutic doses are in the range of 100 mg to 3 g/m2/day Intrauterinegrowth retardation was recorded in two cases in the published literature; intrauterine death in manycases; and functional deficit, defined as a slight retardation in postnatal motor milestones, in asingle case (in this case the patient also had multiple anatomic malformations) Neither growthretardation nor functional deficits are considered representative characteristics of the developmentaltoxicity profile of cytarabine based on the few cases reported In addition to the developmentaleffects, chromosomal abnormalities were also reported in several case reports (Maurer et al., 1971;Schleuning and Clemm, 1987) Paternaluse of cytarabine combined with other antineoplastic drugsprior to conception was said to result in congenital anomalies (Russell et al., 1976) Based on thenumber of published cases of unaffected infants born following first trimester exposure to cytarabine(Lilleyman et al., 1977; Catanzarite and Ferguson, 1984; Reynoso et al., 1987; Juarez et al., 1988;see Schardein, 2000), the risk for developmental toxicity in the human associated with cytarabine

is rather high, especially due to intrauterine death, at approximately 64% The teratogenic risk ofcytarabine is considered by one group of experts to be small to moderate in extent (Friedman andPolifka, 2000) Several thorough reviews of cytarabine combined therapy and pregnancy outcomewere published (Catanzarite and Ferguson, 1984; Caliguri and Mayer, 1989)

CHEMISTRY

Cytarabine is a hydrophobic chemical of near average size as compared with the other humandevelopmental toxicants It is polar and capable of engaging in donor/acceptor hydrogen bondinginteractions The calculated physicochemical and topological properties are as follows

1979; Homer et al., 1979; Pizzuto et al., 1980; Taylor and Blom, 1980; DeSouza et al., 1982; Plows, 1982; Cantini and Yanes, 1984; Fassas et al., 1984; Volkenandt et al., 1987; Juarez

et al., 1988

bone, brain

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REFERENCES

Artlich, A et al (1994) Teratogenic effects in a case of maternal treatment for acute myelocytic neonatal and infantile course Eur J Pediatr 153: 488–491.

leukaemia-Caliguri, M A and Mayer, R J (1989) Pregnancy and leukemia Semin Oncol 16: 388–396.

Cantini, E and Yanes, B (1984) Acute myelogenous leukemia in pregnancy South Med J 77: 1050–1051 Catanzarite, V A and Ferguson, J E (1984) Acute leukemia and pregnancy: A review of management and outcome Obstet Gynecol Surv 39: 663–678.

Chaube, S et al (1968) The teratogenic effect of 1- β -D-arabinofuranosylcytosine in the rat Protection by deoxycytidine Biochem Pharmacol 17: 1213–1216.

DeSouza, J J L et al (1982) Acute leukaemia in pregnancy S Afr Med J 62: 295–296.

Fassas, A et al (1984) Chemotherapy for acute leukemia during pregnancy: Five case reports Nouv Rev.

Kasubuchi, Y et al (1973) Cytosine arabinoside induced microcephaly in mice Teratology 8: 96

Lacy, C F et al (2004) Drug Information Handbook (Pocket), 2004–2005, Lexi-Comp., Inc., Hudson, OH Lilleyman, J S., Hill, A S., and Anderton, K J (1977) Consequences of acute myelogenous leukemia in early pregnancy Cancer 40: 1300–1303.

Maurer, L H (1971) Fetal group C trisomy after cytosine arabinoside and thioguanine Ann Intern Med.

Russell, J A., Powles, R L., and Oliver, R T D (1976) Conception and congenital abnormalities after chemotherapy of acute myelogenous leukaemia in two men Br Med J. 1: 1508

Schafer, A I (1981) Teratogenic effects of antileukemic chemotherapy Arch Intern Med 141: 514–515 Schardein, J L (2000) Chemically Induced Birth Defects, Third ed., Marcel Dekker, New York, pp 591, 593 Schleuning, M and Clemm, C (1987) Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy N Engl J Med 317: 1666–1667.

Taylor, G and Blom, J (1980) Acute leukemia in pregnancy South Med J 73: 1314–1315

Volkenandt, M et al (1987) Acute leukemia during pregnancy Lancet 2: 1521–1522.

Wagner, V M et al (1980) Congenital abnormalities in baby born to cytarabine treated mother Lancet 2: 98–99.

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