Therapy

I I I II 9

Cyclophosphamide (Cytoxan*)
A review on relevant pharmacology and clinical uses
A. Razzaque Ahmed, M.D., and Shiril M. Hombal, M.D. Los Angeles, CA

Cyclophosphamide (Cytoxan; Cy) is an alkylating agent with cytotoxic and

immunosuppressive activities. The parent compound is inactive in vitro and
exerts its biologic activity through metabolites, mainly phosphoramide
mustard generated by hepatic microsomal enzymes. The exact mode of
cytotoxic and immunosuppressive action of Cy at cellular level is not
completely understood. Myelosuppression, hemorrhagic cystitis, alopecia, and
gonadal damage are the main toxic effects. Available data suggest that Cy has
carcinogenic potential in humans. Cy is widely used for cancer chemotherapy.
As an immunosuppressive agent, it is successfully used in certain
nonmalignant diseases in which autoimmune phenomena are established or
suspected in the pathogenesis of the disease. It is the drug of choice in
Wegener's granulomatosis. Extensive efforts are being made to synthesize Cy
analogues with greater selective cytotoxic and immunosuppressive activity.
Ifosfamide, a Cy analogue, appears to possess similar cytotoxic activity with
less myelosuppression. Further research will help in synthesizing a Cy
analogue with specific pharmacologic activity and reduced or absent hamaful
effects. (J AM ACAD DERMATOL11:1115-1126, 1984.)

The observation that mustard gases cause re-
duction in peripheral blood lymphocytes led to the
synthesis of nitrogen mustard. Even though effec-
tive in certain lymphomas, it could not be used
extensively in clinical medicine because of its lim-
ited therapeutic application. Phosphamidase was
observed in certain tumors. This prompted the syn-
thesis of latent, inert derivatives of nitrogen mus-
tard obtained by combining it with phosphoric
acid. The stable inactive oxazaphosphorines thus
formed, once transported into the cell, would be
From the Division of Dermatology, Department of Medicine, Uni-
versity of California School of Medicine, Los Angeles, CA 90024.
Supported in part by United States Public Health Service Grant No.
5S07 RRo5354 and in part by a grant from the Dermatology Foun-
dation of Southern California, Inc.
Reprint requests to: Dr. A. R. Ahmed, UCLA School of Medicine,
CHS 52-121, Los Angeles, CA 90024.
*Mead Johnson & Co., Evansville, IN.
cleaved by phosphamidase in the malignant cells,
releasing cytotoxic amines.*
Over 1,000 compounds were synthesized and
tested. Only four compounds were found to pos-
sess pharmacologic properties. They are cyclo-
phosphamide (Cytoxan, Cy) (1958), trofosfamide
(1972), ifosfamide (1977), and sufosfamide I (Fig.
1; sufosfamide not illustrated). The oxazaphos-
phorine ring formed by the N-propylene group,
with an amidelike bond at one end and an ester
bond at the other end that closes the ring, is of
decisive importance for the antitumor activity.
Even minor deviations in the structure of the ring
abolish this characteristic feature. 1
Cyclophosphamide is the prototype of oxaza-
phosphorines, without direct alkylating action.
The metabolic pathway of cyclophosphamide
*Arnold H, Bourseaux E: Synthesis and degradation of active cy-
tostatic cyclic N. phosphoramide esters of bis (b-chloroethyl)
amine. (Ger.) Agnews Chem 70:539-540, 1958.

1115

1116 Ahmed and Hombal
(Cy) has been extensively studied. The following
scheme is based on experimental studies by Con-
net's et at.2
Cyclophosphamide
I. Activation Cytochrome
P4~ooxidase (liver microsomes)
O:
aldehyde dehydrogenase
4-Hydroxycyclophosphamide 4-ketocyclo-
phospharnide
enzymatic
deactivation
3'5'-exonuclease
Aldehyde oxidase
Aldophosphamide Carboxyphosphamide
Detoxification
Nor-nitrogen mustard
U. Toxification
Phosphoramide mustard + acrolein
Cytotoxic alkylation
Phosphoramide mustard is a powerful alkylating
agent at physiologic pH and is probably the major
biologically active alkylating compound derived
from Cy?
Less than 20% of radiolabled Cy is excreted in
the urine? Cy is not significantly bound to serum
albuminJ There are individual variations in plas-
ma half-life of Cy ranging from 2 to 10 hours, a
Details of cellular transport, conversion, and exact
mode of action of Cy at cellular level are not com-
pletely understood. Phosphoramide mustard has
no significant immunosuppressive effect. 7 Chloro-
acetaldehyde, a strong immunosuppressive agent
released during side chain oxidation of Cy, is
probably responsible for its immunosuppressive
activity.*
In general it is considered that alkylating agents
exert their imrnunosuppressive activity by inhib-
iting nuclear DNA replication. Alkylation of N7
of guanine in DNA can lead to miscoding, de-
struction of the purine ring structure of guanine,
or depurination and DNA cross-linking or block-
age of replication)
The basis for high cytotoxic specificity and car-
*WhitehouseMW, Beck FJ, Kaeena A: Some pharmacological prop-
erties of chloroacetaldehyde on oxidation product and potential
metabolite of eyelophosphamide. Agents Actions 4:34-43, 1974,
Journal of the
American Academy of
Dermatology
cinotoxic selectivity of Cy on tumor cells is not
completely understood. It has been suggested that
the reactions of 4-hydroxycyclophosphamide with
various thiol compounds enhance the stability of
its metabolites in plasma, as well as facilitate their
entry into cells, direct their movement into specific
sites inside the cells, and delay the release of the
alkylating phosphoramide mustard.* Existence of
a 3'-5'-exonuclease, which cleaves 4-hydroxycy-
clophosphamide, releasing phosphoramide mus-
tard, has been demonstrated recently. *
Another hypothesis suggests that normal cells
contain a higher level of the oxidative enzymes
responsible for detoxification of 4-hydroxycyclo-
phosphamide and aldophosphamide than is found
in neoplastic cells. Consequently, neoplastic cells
are subject to greater cytotoxic effect of the phos-
phorarnide mustard, which is released from acti-
vated intermediates. Normal ceils are only mini-
mally affected since the activated Cy intermediates
are preferentially detoxified.2'9
The cytotoxic agents like methotrexate are
termed "phase-specific" since they are active
against ceils in certain phases of their generation
cycle. This was done in order to differentiate them
from agents like Cy, which is ' 'nonphase-specific"
because it can kill the cells during any phase of
the cell cycle. Cy was found to be more effective
against rapidly proliferating cells. ~~ Since Cy is
more effective against proliferative (in cycle)
than nonproliferative (out of cycle) cells, it is
grouped under "cell cycle-specific" antineoplas-
tic agents. ~~ Preferential cytotoxic activity of
Cy against rapidly proliferating lymphocytes has
been demonstrated by 1125UDR labeling of lym-
phocytes. 12
CY EFFECTS ON IMMUNE RESPONSE
Lymphoid tissue
Cy has its greatest effect on B cells with relative
T cell-sparing effect. Selective B cell depletion
from lymph follicles and corticomedullary junc-
tions of lymph nodes and equivalent nonthymus-
dependent areas in spleen has been demonstrated
*Hobarst HJ, Bielieki L, Voelcher G: Mode of action of cyelophos-
phamide. Ninth International Symposium on the Biological Char-
aeterization of Human Tumors, Bologna, 1981.
Volume 11
Number 6
December, 1984 Cyclophosphamide 1117

in mice ~3 and guinea pigs. TM This has been con- ClCH2CH 2

firmed by using Thy-1 antigen as a membrane \N N
marker.t5 Cell cycle specificity of Cy appears to /\/
CICH2CH2,P,
V2
be the prime determinant in killing of immuno- CH2+H20
logically competent cells. 14 ;//'o ....CH2
Cell-mediated immunity Cyclophospharnide
Cy effects on cell-mediated immunity are main-
ly dependent on time at which Cy is administered CICH2C~2
in relation to antigen. Cy, when given to mice after
immunization, inhibits the acquisition of contact
N
/\/ N .CH2
sensitivity response. The tolerance is specific to C' CH2CH~)/;\O ~CH2
the antigen administered but not to related anti- .. . CH2
gens. It possibly represents a combination of clone
Trofosfarnide
deletion and inhibition. ~7
In animal models with a disease resembling se-
vere graft-versus-host disease (GVHD) in humans, CtCHaC~I2
Cy is remarkably effective in preventing mortali-
ty. ~s Cy prolongs homograft survival in mice. z9 /N\ /N C,H2
Mice treated with a single dose of Cy can be ren- CICH2CHz .P, /CH2
dered tolerant to sheep red blood cells (SRBCs)
O//k0 . CH2
when the tolerogen is given in a dose that can elicit
immune response in animals not given the drug? ~ Ifosfamide
Cy-induced tolerance is an aquired immunologic
Fig. 1. Chemical structures for cyclophosphamide,
tolerance with loss of specific immunologic reac- trofosfamide, and ifosfamide.
tivity, 20
The mechanism of Cy-induced immunosuppres-
sion is possibly due to direct cytotoxic effect of use of 4-hydroxyperoxycyclophosphamide, a syn-
the drug on immunocompetent lymphocytes, par- thetic compound that spontaneously hydrolyzes to
ticulafly those that have undergone antigenic dif- 4-hydroxycyclophosphamide in aqueous solution,
ferentiation and division. ~ it is demonstrated that enhancement of cellular
Cy administered in guinea pigs 5 days prior to immune response to SRBCs by this compound
dinitrochlorobenzene (DNCB) sensitization results in vitro is due to selective inactivation of sup-
in augmented and prolonged contact sensitivity, 22 pressor T cells on their precursors, z7
Cy administered in mice before antigenic stimu- Pretreatment of mice with Cy 4 to 7 days prior
lation with SRBCs is shown to release T cells from to Listeria infection results in enhanced cell-me-
the inhibitory influence of humoral responses and diated immunity that coincides with lymphoid hy-
cause enhancement of delayed-type hypersensitiv- perplasiaY
ity. ~3It is suggested that a B cell response to sol- Cy treatment of mice before immunization with
uble antigen modulates a normal cell-mediated im- cell-bound antigens resulted in a strong augmen-
mune response during development of chemical tation of their capacity to generate in vivo antigen-
contact sensitivity in healthy animals. This could specific cytotoxic T lymphocytes, converting their
be completely blocked by Cy treatment prior to in vivo state of low responsiveness into a state of
sensitization. ~ high responsiveness by reconstituting with normal
It is also suggested that effect of Cy on delayed- T cells. 29Experiments demonstrate that precursors
type hypersensitivity (DTH) to SRBCs is due to of suppressor ceils in culture are sensitive to Cy
inactivation of Cy-sensitive suppressor T cells at a dose level that does not abrogate or seriously
that do not affect antibody responseY ,26 With the interfere with the capacity of lymphoid ceils to

1118 Ahmed and Hombal
respond to a normal ceil-mediated cytotoxic gen-
eration system. 28,~o
Antibody production
Pretreatment of rats with Cy can abolish 7s gam-
ma globulin antibody response to antigenic stim-
ulation and can delay the appearance of 19s gamma
globulin antibody response. 31 In animal experi-
ments, pretreatment with Cy causes increased in-
tensity and prolonged Jones-Mote reaction that is
associated with a marked reduction in gamma 1
antibody production) 2Pretreatment of guinea pigs
with Cy causes significant depression of antibody
production with number of antigens. 33
In vitro, Cy can suppress plaque-forming cell
(PFC) responses when added to cell suspensions
that contain plaque-generating B cells.34 Cy blocks
the reexpression of surface immunoglobulin on
cells after modulation of B cell membrane with
F(ab)2 fragments. This may explain the lowering
of B cell tolerance threshold to thymus-indepen-
dent antigens upon Cy administration. 35
In advanced cancer patients pretreatment with
Cy 3 days before sensitization with keyhole limpet
hemocyanin markedly augmented the acquisition
of delayed-type hypersensitivity.36 The exact
mechanism of this phenomenon is not known.
However, experimental evidence suggests that C y
augments immunity by depleting or functionally
impairing or inactivating precursors of suppressor
T cells)7 A heightened lymphocyte responsiveness
to phytohemagglutinin in certain periods, during
therapy with various cytotoxic drags including Cy,
in cancer patients has been demonstrated. In these
patients a diminished activity of suppressor mono-
cytes was observed but a reduction in the concan-
avalin A-induced suppressor T cells could not be
demonstrated.
Human B cells appear to be most sensitive to
Cy, followed in sensitivity by the suppressor T
cells. Helper T cells are relatively resistant. 34
Chronic low-dose Cy therapy has been shown to
have profound and selective suppressor effect on
human B cell function. 3s,39 This may account for
the dramatic efficacy of Cy therapy in certain non-
neoplastic diseases characterized by aberrant an-
tibody production, hypergammaglobulinemia, cir-
Journal of the
American Academyof
Dermatology
culating and deposited immune complexes, or
polyclonal activation of B cells.4~ It has been sug-
gested that Cy inhibits the suppressor cells regu-
lating the IgG2 but not the IgG1 class of antibody. 41
TOXIC EFFECTS
Hematologic effects
Cy inhibition of rapidly dividing cell population
results in consistent and predictable myelosuppres-
sion. In humans after a single dose of intravenous
Cy administration, leukocyte counts begin to fall
by the sixth day, reach nadir between the ninth
and twelfth days and begin to recover by the fif-
teenth day. 42 Reduction in platelets occurs only at
large d o s e s . 42 Cy has an apparent "stem c e l l " -
sparing property. In humans after a single dose of
up to 120 mg/kg, hematopoietic recovery is rapid
and predictable. 43 Cumulative hematopoietic tox-
icity does not occur with repeated Cy d o s e s . 43
Large doses of Cy do not completely eradicate
bone marrow stem cells. Cy-induced aplasia is
reversible. 43
Alopeeia
Some degree of hair loss is encountered even at
a relatively small dose of Cy. Large doses of Cy
cause significant hair loss in 5 % to 30% of patients,
and total alopecia may occur. 44'4~Scalp tourniquets
are reported to reduce alopecia induced by high.
dose parenteral Cy. 46
Nausea and vomiting
During high-dose (>50 mg/kg) therapy, about
65% to 70% of the patients develop severe nausea
and vomiting between 9 and 18 hours after Cy
administration. 47 The degree of nausea and vom-
iting is variable, with some patients tolerating
large doses of Cy with virtually no d i s c o m f o r t :
Cardiopulmonary reactions
Fatal cardiomyopathy during high-dose Cy ther-
apy has been reviewed recently. 4s Lowest fatal
dose reported is 50 mg/kg/day, and cardiac mor-
phology at autopsy examination is characterized
by hemorrhagic myocardial necrosis. Pulmonary
toxicity manifested by pneumonitis, fibrosis, and
chest deformity, though reported, is r a r e : 9'5~
Volume 11
Number 6
December, 1984
Gonadal effects
Gonadal damage is a serious complication of Cy
therapy. Azospermia and amenorrhea, observed in
prolonged Cy therapy, may be irreversible in some
instances. 1 Pathologically in men, marked aplasia
of Sertoli's cells and loss of germinal epithelium
lining the seminiferous tubules are the striking fea-
tures? 1 In women, ovarian atrophy, fibrosis, and
complete absence of follicular structures are the
primary histologic features. ~2 Recovery of repro-
ductive function is unpredictable. Only a few men
and women have regained normal reproductive
function and had normal children after cessation
of Cy therapy. 5t'53's4
Teratogenic effects
Teratogenic potential of Cy in humans is diffi-
cult to evaluate since there are no epidemiologic
data to correctly assess the embryologic risk in
man. Cy is toxic to the fetus and is found to be
teratogenic in a variety of animal species? 5 Limb
reduction has been reported in two infants exposed
to Cy in utero. ~6,57Normal pregnancy and delivery
of a normal child have been observed in patients
on Cy therapy during pregnancy? 8
Mutagenicity and chromosomal effects
There is an increased number of chromosomal
aberrations in the peripheral blood lymphocytes of
children treated with 3 to 5 mg/day of Cy for 6
to 8 months for nonmalignant conditions. 59 This
increase is also seen in patients with rheumatoid
arthritis. 6~Increased levels of sister chromatid ex-
change in peripheral blood lyrnphocytes have been
observed. 61-63
Bladder toxicity
Hemorrhagic cystitis is a major toxic manifes-
tation of Cy therapy. In large studies, the per-
centage of patients developing cystitis has varied
from 0.5% to 40% .64 The occurrence of cystitis in
man does not correlate with dosage of Cy. Children
are affected more frequently. 65 The use of the oral
route as compared to the intravenous route does
not minimize the hazard. 66Evidence indicates that
bladder damage is due to direct effect of toxic
metabolites in the urine, specifically acrolein,
Cyclophosphamide 1119
which is presumed to cause hemorrhagic cystitis,
epithelial regeneration, and hyperplasia with even-
tual bladder fibrosis. 67 It has been suggested that
N-acetyl-cysteine administered during Cy therapy
protects against Cy-induced cystitis by chemically
interacting with acrolein in the bladder, thereby
reducing its chemical interaction with bladder mu-
cosa. 68Excessive fluid intake and frequent voiding
help to prevent the development of cystitis.
Carcinogenic effects
There have been at least thirty case reports of
malignancy in patients treated with Cy for non-
malignant diseases, mainly rheumatoid arthritis
and glomerulonephritis, and at least eighty-three
case reports of second malignancy following Cy
therapy for malignant diseases. 69 Significant in-
cidence of bladder carcinoma, non-Hodgkin's
lymphoma, and squamous cell carcinoma of the
skin has been observed in patients treated for non-
malignant diseases. 7~
The incidence of a second cancer is also in-
creased in Cy-treated cancer patients. These ma-
lignancies have been bladder cancer, acute leu-
kemias, and reticulum cell sarcomas in some
unusual locations. 69'72 A ninefold increase in the
incidence of bladder carcinoma has been reported
in Cy-treated cancer patients as compared to
those who received alternate chemotherapy. 73 Five
cases of bladder cancer have been reported in
patients treated with Cy for nonmalignant dis-
eases .74-77
Studies of occupational exposure to chemical
carcinogens indicate that the interval between first
exposure to the chemical and the subsequent de-
velopment of bladder cancer may take as long as
45 years. 78 Since Cy-treated patients with non-
malignant diseases may live considerably longer
than Cy-treated cancer patients, risk of bladder
cancer in Cy-treated patients with benign illness
is likely to be high in the future. Although a grow-
ing number of reports seem to implicate Cy with
carcinogenic potential in humans, clinical data re-
ceived so far appear to be too sparse to determine
definitely whether this is due to direct carcinogenic
effect, to immunosuppressive effect, or to a com-
bination of both.

1120 Ahmed and Hombal
Miscellaneous toxic effects
In patients receiving parenteral doses of Cy ex-
ceeding 50 mg/kg, impaired water excretion re-
sulting in a variable degree of water intoxication
has been reported29 The syndrome is usually self-
limited. Evidence of hepatotoxicity f r o m Cy ther-
apy has been reported. 8~ Feverfl'- mucosal ul-
ceration, skin pigmentation, anaphylaxis, 83 urti-
caria, 84 acute oropharyngeal dysesthesias, 85 nail
pigmentation,86 and transient cerebral dysfunc-
tion87have been rarely associated with C y therapy.
Dose
The usual range of intravenous dose for cancer
patients with no hematologic deficiency is 10 to
15 mg/kg repeated thrice weekly. W h e n therapy
is given orally, the dose is 1 to 5 mg/kg/day,
depending upon the patient's tolerance. 87 Immu-
nosuppressive action of Cy results in increased
susceptibility to bacterial, fungal, and viral infec-
tions, especially in patients receiving concomitant
steroid therapy. In chronic oral therapy for non-
malignant diseases, total leukocyte c o u n t is a good
objective guide for regulating the maintenance
dose. A leukocyte count of 3,000-4,000/mm 3
(granulocyte count > 1,000/mm3) is considered to
be adequate to prevent the risk of serious infec-
tions. ~ It is important to note that changes in leu-
kocyte count usually lag 8 to 12 days after Cy dose
is given.43
Therapeutic uses
A broad range of human tumors respond to Cy.
These include malignant lymphomas, leukemias,
multiple myeloma, neuroblastoma, retinoblasto-
ma, sarcomas, carcinomas of the ovary, testis,
breast, and lung, and most cases of mycosis fun-
goides. 6~ In cancer chemotherapy, Cy is usually
administered concurrently or sequentially with
other antineoplastic agents. In mycosis fungoides
good response to Cy therapy has been reported by
many investigators. 8992 In one report, C y therapy
resulted in only partial improvement. 93 In most
reports, Cy alone was usedg~-93;however, combi-
nation of Cy with epipodophyllotoxin (VP-16-
213)~ and chlorpromazine9~ has been used suc-
cessfully by some investigators. The combination
of Cy with epipodophyllotoxin (VP-16-213) was
Journal of the
American Academy of
Dermatology
found to be effective in inducing remission but
was not effective in maintaining a prolonged re-
mission. 89 In another report, the combination of
Cy with chlorpromazine was found to produce lon-
ger remission than Cy therapy alone.g~
As an immunosuppressive agent, Cy appears to
be the most potent drug in several studies. 94 As an
immunosuppressive agent, Cy is used in clinical
medicine in certain autoimnmne diseases in which
immunologic surveillance systems of the body are
implicated in their pathophysiology.
Autoimmune skin diseases
Stimulus to the trial of Cy in pemphigus vulgaris
(PV) was prompted by the evidence that PV in-
volves an autoimmune phenomenon in its patho-
genesis in which level of autoantibody titer is cor-
related with the severity of the skin disease, 95 In
most studies, Cy was indicated in PV patients who
had developed steroid complications or could not
tolerate large maintenance doses of corticoste-
roids9699 and in patients where steroid therapy had
failed to control the disease. 100
In one study, ~~176 initial combined treatment
with prednisone and Cy was used with the pre-
sumption that the combination of Cy and predni-
sone has a stronger effect on suppressing abnormal
B cells. In all cases, addition of Cy to the pred-
nisone therapy resulted in satisfactory control of
the disease and/or permitted a reduction in the
prednisone dose. When Cy was used alone to con-
trol active disease, it was found to be ineffec-
tive. 103Successful use of prednisone and Cy in five
patients with bullous pemphigoid has been re-
ported. 98.100
Systemic lupus erythematosus (SLE)
Since the introduction of corticosteroids in SLE,
steroids have remained the cornerstone of therapy
in SLE.I~ In experimental studies, Cy decreased
the incidence of severe spontaneous autoimmune
renal disease from 100% to 6.7% in female (NZB
& NZW) FI hybrid mice and greatly reduced the
mortality.t~ Cy employed as a sole agent in SLE
did not produce favorable results. 1~ In various
controlled and uncontrolled studies, Cy in com-
bination with prednisone was found to be benefi-
cial. ~~176 In one study, Cy was useful as an
Volume 11
Number 6
December, 1984
accessory drug only and helped in lowering the
maintenance dose of prednisone. ~~ In recent re-
ports, no significant differences in patient survival
or renal function were observed in patients with
diffuse proliferative lupus nephritis who received
high doses of prednisone alone or combined pred-
nisone and Cy therapy. 1.,112 Recurrences and trend
toward progressive renal disease, however, were
less in Cy-treated patients. ~lZ
Further study with an average 6-year follow-up
did not reveal any significant beneficial effect of
combined prednisone and oral Cy therapy on the
development of end stage renal disease or in re-
ducing the total patient deaths, ~13Adding azathio-
prine to Cy and prednisone therapy did not show
any advantage or beneficial effects. ~14 In another
controlled study after 6.5 years' follow-up with a
mean observation period of 42 months, only mar-
ginal benefits were observed in patients treated
with Cy and azathioprine or Cy alone when com-
pared to patients treated with prednisone only, but
no definite conclusion could be reached.~5
Rheumatoid arthritis
In some patients with rheumatoid arthritis, the
disease proceeds aggressively, resulting in pro-
gressively destructive joint disease with systemic
lesions refractory to conventional drug therapy. ~6
In various controlled 117-119 and uncontrolled 12otrials
of Cy therapy in severe progressive rheumatoid
arthritis patients therapeutic efficacy of long-term
oral Cy therapy has been established. Cy in an
average dose (> 1.8 mg/kg/day), sufficient to in-
duce moderate leukopenia, over a period of a few
months is highly effective in reducing the activity
and symptoms of severe rheumatoid arthritis, ~8
Preliminary general guidelines for the use of cy-
totoxic agents in rheumatoid disease have been
proposed. ~20Currently, azathioprine appears to be
preferable to Cy in rheumatoid arthritis due to few-
er short-term side effects. 121
Systemic vasculitides
Systemic necrotizing vasculitis consists of a
group of disorders characterized by severe dis-
seminated necrotizing vasculitis of the viscera with
or without skin involvement.~z2 Complete and of-
ten dramatic remissions are reported with corn-
Cyclophosphamide 1121
bined prednisone and Cy therapy in severe nec-
rotizing vasculitis resistant to steroid therapy, m
Cy is probably the drug of choice in most of the
severe steroid-resistant systemic vasculitides that
involved medium-sized muscular arteries. ~23
Use of Cy in vasculitides syndromes was re-
viewed recently. ~22Successful Cy therapy has been
reported in other granulomatous vasculitides TM
and in steroid-resistant severe polyarteritis no-
dosa. t2s Cy is the cytotoxic drug of choice in
Wegener's granulomatosis. ~22In a study of eighty-
five patients after a 2 1-year follow-up, therapeutic
efficacy of Cy was clearly established in Wege-
ner's granulomatosis. 126 Long-term complete re-
missions even after cessation of therapy have been
reported. Successful treatment with Cy of a group
of patients with long-term seropositive rheumatoid
arthritis, complicated by severe vasculitis, has
been reported. 1z7
Miscellaneous
Cy has been used in various dermatologie dis-
eases and there have been numerous reports of its
success in various diseases. Successful results
have been obtained in two cases of pyoderma gan-
grenosum unresponsive to steroid therapy. 12s,129
Improvement was reported in a patient with pso-
riasis and arthritis when conventional therapy with
steroids was not effective. ~3oSignificant improve-
ment has been reported in a patient with ichthyosis
linearis circumflexa treated with low-dose Cy. TM
Improvement of symptoms and long-term remis-
sions have been reported in patients with severe
intractable eczema treated with Cy after prolonged
systemic and topical steroids had failed to produce
adequate response.~2
Treatment with Cy andJor colchicine has been
reported to suppress visual symptoms successfully
and to prevent recurrent episodes of iridocyclitis
or uveitis with hypopyon in Beh~et's disease. ~3~-~3~
In numerous other conditions success with Cy
has been reported. These include polymyositis, 136
dermatomyositis, 137 essential mixed cryoglobu-
linemia,~38 nephrotic syndrome,t39.~40 refractory
thrombocytopenic purpura, 14t,14z severe aplastic
anemia, ~43 active chronic hepatitis, TM idiopathic
pulmonary hemosiderosis, 14s plasma cell intersti-
tial pneumonia and macroglohulinemia~46 and

1122 A h m e d and Hombal
s c l e r o d e r m a . ~47 C y is b e i n g used increasingly as
an i m m u n o s u p p r e s s i v e a g e n t f o l l o w i n g organ
transplantation. 148
E x t e n s i v e efforts are b e i n g m a d e to synthesize
C y analogues with greater selective cytotoxic and
i m m u n o s u p p r e s s i v e activity with lesser toxic and
a d v e r s e side effects. Clinical and pharmacologic
aspects o f C y analogue i f o s f a m i d e have b e e n re-
v i e w e d recently. 149 E x t e n s i v e clinical trials are
being c o n d u c t e d with i f o s f a m i d e . Available clin-
ical data d e m o n s t r a t e no instance in which ifos-
f a m i d e is inferior to C y as an antineoplastic agent.
I f o s f a m i d e has potentially reduced myelotoxic
properties, and c a r d i o t o x i c and hepatotoxic effects
are not r e p o r t e d so far. I n c i d e n c e o f urinary tox-
icity a p p e a r s to b e greater than with the use o f Cy.
With e x t e n s i v e r e s e a r c h being done in cancer
c h e m o t h e r a p y , new insight is likely to be gained
to the p h a r m a c o l o g i c basis o f c o m p a r a t i v e selec-
tivity and clinical e f f e c t i v e n e s s o f p h o s p h o r a m i d e
m u s t a r d s , and future p r o s p e c t s o f synthesizing a
truly c u r a t i v e C y analogue with structural modi-
fications a p p e a r to be e n c o u r a g i n g .
REFERENCES
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2. Connors TA, Cox PJ, Farmer PB, etal: Some studies
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metabolism of cyclophosphamide and isophosphamide.
Biochem Pharmaeol 23:115-129, 1974.
3. Colvin M, Brundrett RB, Kan HN, et al: Alkylating
properties of phosphoramide mustard. Cancer Res
36:1121-1126, 1976.
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ABSTRACTS
The effect of povidone-iodine paint on fungal
infection
Manna VK, Pearse AD, M a r k s R: J Int Med Res
12:121-123, 1984
Although povidone-iodine paint may cure pityriasis ver-
sicolor, it is messy.
P.C.A.
A survey of dermatophytes isolated from human
patients in the United States from 1979 to 1981
with chronological listings of worldwide incidence
of five dermatophytes often isolated in the United
States
Sinski JT, Flouras K: M y c o p a t h o l o g i a 85:97-120,
1984
At intervals, the dermatophytes recovered from human
patients in the United States are reviewed, as collected by this
mail survey over 1979-1981. Trichophyton rubrum won eas-
ily as most common isolate. Trichophyton tonsurans was
emerging as the principal new cause of tinea capitis. The
incidence of Trichophyton mentagrophytes infections, as the
authors note, is grossly underreported in this sort of study.
Microsporun~ attdouini infections are uncommon now, but
Microsporum canis isolates may be increasingly important.
P.C.A.
Identity of the proliferating cell nuclear antigen
and cyclin
M a t h e w s M B , Bernstein R M , Franza BR Jr: Nature
309:374-376, 1984
The study of growth regulation and cellular transforma-
tion, as shown in this paper, is most promising for the dis-
covery of future "wonder drugs" on which the successful
practice of medicine relies.
P.C.A.
Journal of the
American Academy of
Dermatology
148. Starzl TE, Groth CG, Putman CW, et al: Cyclophos-
phamide for clinical renal and hepatic transplantation.
Transplant Proc 5:511-516, 1972.
149. Colvin M: The comparative pharmacology of cyclo-
phosphamide and ifosfamide. Semin Oncol 9:(suppl
4):1-102, 1982.
A comparison of acyclovir cream versus placebo
cream versus liquid nitrogen in the treatment of
viral plantar w a r t s
Gibson JR, Harvey SG, Barth J: Dermatologica
168:178-181, 1984
In this study of treatment for plantar warts, acyclovir
cream was not hetter than placebo cream. Only eleven of
twenty-seven patients treated with liquid nitrogen were cured,
but this included failures from other groups. Honest prospec-
tive studies usually do not show any therapy to be impressive
in curing well-established plantar warts in adults, as we see
here again.
P.C.A.
Langerhans' cells and T cells in human skin
tumours: An immunohistological study
Gatter K C , Morris HB, Roach B: Histopathology
8:229-244, 1984
Langerhans' cells may be decreased in number and quality
in malignant tumors of the skin, and, in contrast, not de-
creased (or may even be increased) in some benign tumors.
Further confirmation and more detail is to be sought. If en-
tirely true and consistent, this would be an extremely useful
criterion.
P.C,A.
Pseudomonic acid--a new antibiotic for skin
infections
Reilly GD, Spencer RC: J Antimicrob C h e m o t h e r
13:295-298, 1984
Pseudomonic acid, a new topical antibiotic, seems to be
effective for ordinary pyoderrnas.
P.C.A.