PART TWO
Diagnostic Cytology
Antineoplastic Chemotherapy
C hem otherapeutic changes share m an y o f th e features o f radia-
tio n changes. The k illin g o f tu m o r cells fo llo w s first-ord er k in e t-
ics, k illin g a certain percentage o f tu m o r cells after each dose.
T his p h en om en on is related to dose and phase o f the cell cycle.
There are a n um b er o f general categories o f chem otherapeutic
agents. These include a lkyla ting agents, antim etab olites, natural
products, b iolog ic response m od ifiers, m iscellaneous agents,
and h o rm o n a l agents.
T u m o r cell p o p ulatio ns are asynchronous heterogeneous
p op ulatio ns o f cells. M a n y o f the alkyla ting agents, antim e ta b o -
lites, and n atural products are cell cycle-specific. Each m ay act at
d istin c tly d iffe re n t phases o f the cell cycle o r at m ore th a n one
p o in t in the cell cycle. C o m b in a tio n s o f the therapeutic agents
w h ic h have d iffe re n t targets often contain those th a t act at d if-
ferent phases o f the cell cycle (Table 30.5) . Table 30.6 identifies
those chem otherap eutic agents and ra d ia tio n th a t act at specific
stages o f the cell cycle.52
C hem otherap eutic agents tend to affect a sm a lle r n um b er
o f cells th an ra d ia tio n changes. T he cytologic changes are seen
in few er cells th an in irradiated specimens. Since chem othera-
peutic agents are ad m inistered system ically, changes at rem ote
sites are m ore com m on. B oth ra d ia tio n and chem otherap y are
m utagenic. The ris k o f o th e r m alignancies is increased 2 -4 years
after chem otherapy. T his is m ost evident w ith a lkyla ting agents.
T he effects o f second m alig nancy m ay be enhanced in com b ina-
tio n w ith radiotherapy. The m ost c om m o n second m alignancies
includ e leukem ias, lym p hom as, and squam ous cell carcinom a.
T his contrasts w ith radiated tissues, fo r w h ic h carcinom as and
sarcomas are m ost likely.
A p p roxim a te ly 35 anticancer drugs were in use in 1992. The
current n um b er o f anticancer drugs is close to 100.53 Assess-
m e n t o f th e ir effects is dependent o n eith er clonogenic assays
o n tu m o r stem cell p o p ulatio ns o r nonclonog enic assays. N o n -
clonogenic assays are applied against an unselected tu m o r cell
p o p u la tio n (Table 30.7). This m ost closely resembles tu m o r cells
in vivo. M icroscopic evidence o f cell degeneration is one o f the
nonclonog enic assays. C hem otherapeutic secondary effects m ay
be fo u n d in samples fro m any b o d y site b u t are m ost fre q ue ntly
noted in samples fro m the cervix, lu n g ,54 and bladder. These sites
are also am ong the m ost fre q ue ntly sam pled sites fo r cytology.
Table 30.5 Chemotherapeutic Agents
Agent(s)
Effect
Dactinomycin
Inhibits DNA, RNA, protein
Doxorubicin (Adriamycin), BCNU
Intercalate DNA
Bleomycin, nitrogen mustard
Single- and double-stranded
breaks
Cisplatin
Intra- and interstrand cross-links
Vincristine, vinblastine
Bind tubulin in mitotic spindle
5-Fluorouracil
Inhibits thymidylate synthetase
Hydroxyurea
Inhibits ribonucleotide diphos-
phate reductase
Methotrexate
Inhibits dihydrofolate reductase
Etoposide
Topoisomerase II inhibitor
Paclitaxel (Taxol)
Tubulin binding
Key features of chemotherapy
• C e ll e nlarg em ent;
• H yp e rc h ro m a sia ;
• S m udged c h ro m a tin ;
• N u c le a r and c yto p la sm ic v a c u o liz a tio n ; and
• D yscohesion.
Bleomycin
B leom ycin is an antineop lastic and a n tim ic ro b ia l polypeptide
a n tib io tic isolate fro m the fungus
S tre p to m yc e s v e rtic illu s .
Briefly,
the m echanism o f action is the b in d in g o f b leo m yc in to gua-
n in e bases in D N A w ith the o xid a tio n o f Fe2+
(ferrous iro n ) to
Fe3+
(ferric iro n ). T he liberated electron is accepted b y oxygen
to fo rm superoxides and hyd roxyl radicals. These active oxygen
interm ediates attack D N A bases, leading to single- and d oub le-
stranded D N A breaks and d eletions.55 T he p rim a ry to x ic ity o f
b leom ycin is a subacute o r chronic p n e u m o n itis w ith progres-
sio n to in te rs titia l p n eum onitis.
Chest radiography shows b ib asilar p u lm o n a ry infiltrate s
th a t m ust be d ifferentiated fro m m etastatic tu m o r, infectious
processes such as
P n e u m o c y s tis c a r in ii
and cytom egalovirus, and
ra d ia tio n injury. D iagnosis is often m ade b y open lun g biopsy.
Less aggressive diagnostic m ethod s includ e sputum , b ron c hial
lavage, brushings, and FN A cytology.56
B leom ycin to x ic ity is fatal in ab out 1 -2 % o f patients. A n
a d d itio na l 2 -3 % o f patients experience n o n le th a l p u lm o n a ry
fibrosis. T o xic ity u su ally does n o t occur b e lo w a c um ulative dose
o f 400 units. However, M cLeod and associates reported th a t a
case occurred after a dose o f o n ly 60 units, suggesting th a t a
true th resh old m ay n o t exist.57 O th e r factors m ay be synergistic
and increase th e incidence o f bleom ycin-ind uced p u lm o n a ry
toxicity. These include age (old e r th a n 70 years), p rio r rad ia tio n
Table 30.6 Cell Cycle-specific Therapeutic Effects
Phase
Therapeutic agents
G1
Radiation, alkylating agents, cisplatin
S
Docetaxel, methotrexate, Ara-C, 6-thioguanine,
hydroxyurea, vinblastine, vincristine, doxorubicin
G2
Paclitaxel, bleomycin
M
Radiation and alkylating agents
Table 30.7 Clonoge■ nic and Nonclonogenic Assays
Clonogenic
• Stem cell proliferation
• Colony formation
Nonclonogenic
• Microscopic
• Trypan blue exclusion
• MTT assay
• Macromolecular synthesis (DNA, RNA, protein)
• Proliferation assays
• Assays of apoptosis
958
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