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288 Nuclear Medicine Physics

context, data from animal models show that 5-chloro-6-(2-iminopyrrolidin-

1-yl)methyl-2,4(1H,3H)-pyrimidinedione, a speciﬁc inhibitor of thymidine

phosphorylase, is able to reduce tumor size [170].

Additionally, since thymidine phosphorylase also catalyzes the reverse

reaction, that is, the conversion of thymine to thymidine, it may also help

to retain within the cell therapeutic thymidine analogs such as capecitabine,

which is converted into ﬂuorouracil.

Analogs radiolabeled with astatina-211 (

211

At), iodine-125 (

125

I), or iodine-

131 (

131

I) can also be used both as therapeutic agents to destroy tumor cells

and as tracers to identify tumors with high levels of thymidine phosphorylase

that can be treated and/or to monitor the therapeutic response and tumor

angiogenesis.

6.4.7.2 Tyrosine Kinase

Tyrosine kinase inhibitors such as geﬁtinib (Iressa

) or erlotinib (Tarceva

)

showed that they are capable of preventing tumor growth. The effectiveness

of this therapy can be assessed using a derivative of tyrosine labeled with

99m

Tc, using cyclam (1,4,8,11-Tetraazacyclotetradecane) as a chelating agent.

Studies performed in vitro showed a good correlation between the cel-

lular uptake of

99m

Tc-cyclam-tyrosine and the expression of the protein

quantiﬁed by Western blot. Consequently, tumors with a high expression

of tyrosine kinase also show a good correlation with data obtained from cell

cultures [170].

Studies with

99m

Tc-cyclam-tyrosine indicated that the tracer can be useful in

the selection of patients undergoing therapy with tyrosine kinase inhibitors.

6.4.8 Tumor Hypoxia

Tissue hypoxia is characterized by a decrease in the partial pressure of oxygen

in the tissues; it underlies the pathogenesis of several diseases, and it has also

been considered essential for the growth of malignant solid tumors. In cancer,

tumor hypoxia is one of the most important factors implicated in resistance

to radiotherapy and conventional chemotherapy, resulting in higher local

tumor recurrence. Moreover, it is known that hypoxia also induces angiogen-

esis, which contributes to cancer invasion and metastization, which is also

associated with poor prognosis.

Tumor resistance related to hypoxia can be overcome through the use

of hypoxic cell radiosensitizers or hyperbaric oxygen, as low levels of

hemoglobin and low tumor partial pressure of oxygen (pO

) are associated

with higher resistance to treatment.

Getting information about tumor hypoxia status, so as to predict the out-

come of radiotherapy or the possible use of radiosensitizers, is now a reality,

through either biochemical analysis or noninvasive functional imaging [173].

Imaging Methodologies 289

There is a nuclear protein called hypoxia-inducible factor (HIF), which

provides information on intracellular hypoxia status. This protein is com-

posed of two subunits, alpha and beta. The alpha subunit is responsible

for a speciﬁc hypoxia response, but the beta subunit has no such speci-

ﬁcity. Under normoxia conditions, depending on the von Hippel–Lindau

tumor suppressor protein (pVHL), the subunits are rapidly degraded by

the ubiquitin–proteasome pathway. Under hypoxia conditions, the subunits

are stabilized and translocated to the nucleus, where the β-subunit can be

dimerized with a DNA molecule.

In terms of detection, the HIF alpha subunits are not present in most nor-

mal human tissues, but they are expressed in many malignant tumor cells,

particularly in areas adjacent to necrosis. This pattern is seen in prostate,

breast,lung, gastrointestinaltract, brain, ovary, melanoma, and mesothelioma

tumors. In clear-cell renal carcinoma and hemangioblastoma, it is mainly seen

throughout the tumor mass. In brain tumors, since necrosis and hypoxia are

histological invasiveness hallmarks, the degree of HIF α-subunit expression

is correlated with the tumor type.

NM is important, as it is possible to radiolabel some molecules involved

either in the intracellular pathways of hypoxia or in the impact on other

metabolic routes. This labeling means that an image can provide qualitative

and quantitative information about whether there is tumor hypoxia.

It is known that hypoxic tissues can take up bioreductive molecules that

contain an imidazole group, such as misonidazole. These molecules have the

capacity to accept an electron,with the consequent production of a free radical

anion that, after reduction, is incorporated in the constituents of the cell if

it is under hypoxic conditions. Consequently, the quantity of bioreductive

molecules taken up by hypoxic cells can be seen as a direct sensor of oxygen

partial pressure in tissues.

The ﬁrst molecules developed with the objective of being used as molecular

imaging agents were ﬂuoromisonidazole (FMISO) and ﬂuoroerythronitroim-

idazole (FETNIM), both having a ﬂuorine atom. This ﬂuorine atom in

molecules means that they can be labeled with

F, to form the

F-FMISO

and

F-FETNIM complexes, respectively [168,174,176].

With the same goal, other molecules that do not contain an imidazole

group were developed. They include iodoazomycin arabinoside (IAZA)

and iodovinylmisonidazole (IVM). These molecules have an iodine atom,

enabling them to be labeled with different iodine isotopes, including

123

I and

124

I. This labeling enables them to be used in NM by single photon emission

(when labeled with

123

I) or PET, if

124

I is used.

There are other compounds, not derived from nitroimidazole, that can be

used for the same purpose. The ones giving the best results were 4,9-diaza-

3,3,10,10-tetramethyldodecan-2,11-dione dioxime, known as HL-91, which

can de labeled with

99m

Tc, and Cu(II)-diacetyl-bis(N-4-methylthiosemi-

carbazone) (ATSM), which can be labeled with several copper isotopes [176].

290 Nuclear Medicine Physics

More recently, two compounds have been developed,

F-ﬂuoro-PR-170

for use in PET and SR 4554 (N(2-hydroxy-3,3,3-triﬂuoropropyl)-2-(2-nitro-1-

imidazolyl)acetamide) for use in nuclear MRI. This compound also appears

to have potential to be labeled with positron emitters and thus, can be used

as a PET tracer [168].

6.4.9 Tumor Angiogenesis

Angiogenesis is the proliferation of endothelial and smooth muscle cells to

form new blood vessels. This neovessel proliferation is a crucial factor in the

metastatic process and has an impact at two levels. First, the new vessels

provide the main route through which tumor cells leave the primary tumor

site and spread to other parts of the body, with the possibility of distant

secondary locations. Second, the new vessels supply tumor tissue with the

oxygen that enables the primary tumor growth more.

The growth of these new blood vessels is mediated and controlled by sev-

eral angiogenic growth factors, particularly the vascular endothelial growth

factor (VEGF), some cellular receptors such as estrogen receptors, and some

adhesion molecules such as integrin αvβ3. This integrin is expressed in vas-

cular endothelial cells only during angiogenesis and vascular remodeling,

particularlyin themetabolic pathwaysstimulated by VEGF; it isnot expressed

in mature vessels or in the nonneoplastic epithelium. Integrin vβα3 also

binds to several ligands if they contain the pattern-Arg-Glu-Asp-(RGD) in

the extracellular matrix [177].

With regard to this bond, it was shown that disruption of this ligand inter-

action by competitive antibody binding blocks the proliferation of new blood

vessels. This was clinically used with the development of a new therapeu-

tic monoclonal antibody, called LM609, which prevented the proliferation of

new vessels.

An in situ tumor can grow up to 1–2 mm without additional nourishment

from the blood supply. However, the oxygen needs increase as it grows, and

this leads to the appearance of a more acidic microenvironment that induces

tumor cells to produce angiogenic factors which stimulate the development

of new vessels. The neovascularization allows for tumor expansion and also

provides an escape route for tumor cells to travel to other areas of the body, a

long way from the primary tumor location, to produce new tumor foci: these

are metastases. This process is particularly true for tumors with high vascular

density that show a higher incidence of metastasis than poorly vascularized

tumors.

This type of tumor expansion is the basis of the development of angio-

genesis inhibitors that are a highly promising new approach for anticancer

therapy. Four types of molecules can be considered as antiangiogenic ther-

apeutic agents. They are antibodies, protein fragments, modulation of the

Imaging Methodologies 291

ﬁbroblast growth factor (FGF), and synthetic small molecules. In the case of

antibodies,we have anti-integrins,anti-EGFR (epidermalgrowthfactorrecep-

tor), anti-VEGF monoclonal antibody, and antiendoglin glycoprotein. In the

case of protein fragments, plasminogen and collagen can be used. In relation

to FGF modulation, interferons are very important molecules. As far as small

synthetic molecules are concerned, protease inhibitors, urokinase inhibitors,

cyclooxygenase inhibitors, and tyrosine kinase inhibitors are new approaches

that must be considered [177].

Based on these new approaches, several studies using cyclic peptides with

the RGD sequence labeled with

99m

Tc, and

111

In are now in progress to

assess angiogenic status through a functional image.

In fact, if the results obtained from animal models conﬁrm the high tumor

uptake of such molecules, they could be used as image tracers for diagnosis

and also to give information about the therapeutic response to αvβ3 inte-

grin antagonists. One of these molecules is ethylenedicysteine endostatin

(EC-endostatin) labeled with

99m

Tc (

99m

Tc-EC-endostatin). This complex is

under study as a potential noninvasive image tracer, able to give qualitative

and quantitative information about the tumour’s response to antiangiogenic

therapy. This is because in vitro cell viability and TUNEL (terminal deoxy-

nucleotidyl transferase biotin-dUTP nick end labelling) assays indicate no

clear difference between EC-endostatin and endostatin. Moreover, biodistri-

bution of

99m

Tc-EC-endostatin in tumor-bearing rats showed that the tumor

to normal tissue count ratio increased with time, which was conﬁrmed by

planar images. These images reveal that the tumors were well visualized

two hours after

99m

Tc-EC-endostatin administration. In addition, this uptake

by the tumor can be used to assess the effectiveness of antiangiogenesis

therapy.

Cyclooxygenase-2 (COX-2) is another molecule with an important role

in angiogenesis and, indirectly, in cancer progression. Since many tumours

express COX-2, functional images obtained with a COX-2 inhibitor such

as Celebrex (CBX) labeled with

99m

Tc (

99m

Tc-EC-CBX) may give noninva-

sive information about tumor COX-2 expression as well as information about

clinical responses to anti-COX-2 therapy or even about patient selection for

treatment with these agents [170].

Another important factor that plays an important role in cell division,

tumor progression, angiogenesis, and metastasis is EGFR. Since many tumors

express EGFR on their surface, the functional images using monoclonal

antibodies that target the EGFR, such as the chimeric monoclonal antibody

C225 labeled with

99m

Tc (

99m

Tc-EC-C225), may give noninvasive information

about EGFR expression. This information can also be useful for the evalua-

tion of clinical responses to anti-EGFR therapy or even for patient selection

for treatment with this kind of molecule [170].

Results alreadyobtained in nude mice bearing xenografts showed that C225

in combination with cytotoxic drugs or with radiotherapy is effective in the

eradication of well-differentiated EGFR-expressing tumors.

292 Nuclear Medicine Physics

6.4.10 Apoptosis

Apoptosis, which is programmed cell death or cell suicide, is an active energy-

dependent mechanism for the removal of injured, infected, or immuno-

logically recognizedas harmful or superﬂuous cells.Although a large number

of stimuli can initiate the apoptotic process, they all culminate in caspase

cascade activation. The activation of these proteases leads to irreversible

changes in cell components, such as cytoskeletal disruption, chromatin

clumping, internucleosomal DNA cleavage, and, eventually, disintegration

of the cell into small membrane-bound leftovers targeted for quick removal

by macrophages. The apoptotic process is fast and is not usually accompanied

by an acute inﬂammatory response.

The role of apoptosis has been demonstrated in a great variety of phys-

iological processes, including during embryogenesis, in postnatal brain

remodeling, in the development of immune tolerance through clonal deletion

of T cells, and in the turnover of senescent cells in the intestinal mucosa.

In oncology, apoptosis is also important in a wide variety of malignant

tumors, particularly in hypoxic regions adjacent to areas of necrosis, which is

currently the endpoint of most forms of anticancer therapy.

With regard to anticancer therapy, some authors see apoptosis as the most

critical factor inﬂuencing tumor sensitivity or resistance to chemotherapy. In

some cancers, therefore, the apoptotic index of the tumor can be considered

as a prognostic factor of the clinical response to chemotherapy and as overall

survival.

It is known that apoptosis is the major mechanism in cell death after radio-

therapy. In fact, doses of 1 to 5 Gy induce apoptosis, which appears about 1

to 2 h after irradiation and reaches a maximum almost 3–6 h after irradiation.

The intensity of apoptosis can be quantiﬁed by using a ﬂuorescent TUNEL

stain and Bcl-2 (B-cell leukemia/lymphoma 2) and Bax (Bcl-2-associated-X-

protein) by semiquantitative immunohistochemical assays [170].

One of the characteristics of normal membranes is that phosphatidylserine,

anative phospholipidmembrane anion, is generally limitedto theinner leaﬂet

of the plasma membrane lipid bilayer. However, in cells that are in apoptosis,

phosphatidylserine is selectively and quickly translocated to the outer leaﬂet

and is, thus, exposed on the membrane surface.

Annexin-V is an endogenous human protein that is able to bind with very

high afﬁnity to exposed phosphatidylserine. This characteristic makes it an

apoptosis marker which has been used after being labeled with radioac-

tive isotopes to obtain functional images that show whether apoptosis is

occurring at the site under study. For this purpose, annexin-V was labeled

with iodine and technetium using ethylenedicysteine (

99m

Tc-EC-annexin-V)

or hydrazinonicotinamide (

99m

Tc-HYNIC-annexin-V) as chelating agents for

labeling with

99m

Tc. This type of labeling yields functional information related

Imaging Methodologies 293

to apoptosis for monitoring the dynamics of cell death induced by chemother-

apy and/or radiotherapy, and it also assesses the effectiveness of therapies

[170,178].

Results obtained in animal models where annexin-V labeled with

99m

were used showed that it is taken up by heart, lung, and liver allografts;

by arteriosclerotic plaques; and neonatal rabbit brain after unilateral carotid

artery ligation to induce cerebral hypoxia.

Similarly, studies in humans show increased annexin-V uptake in a cardiac

allograft recipient when there is histological evidence of transplant rejection

as well as in some patients with acute myocardial infarction.

Also, in vitro studies conﬁrm the uptake of annexin-V labeled with

99m

Tc by

breast cancer cell lines when they are exposed to paclitaxel and 10 to 30 Gy

of radiation. Similar results were obtained in breast tumor bearing rats when

they were treated with paclitaxel.

The results obtained so far indicate that annexin-V uptake correlates well

with the extent of cell death but is not speciﬁc to apoptosis, because it can

also occur in cell necrosis.

6.4.11 Multiple Drug Resistance

Multiple drug resistance (MDR) is the development of cross-resistance to

several cytotoxic drugs, not related either structurally or functionally after

tumor exposure to an individual cytotoxic drug [179–181].

In clinical practice, chemotherapeutic protocols almost always involve a

combinationof drugs thatacton different cellular targetstomaximize the ther-

apeutic effect. This means that the drugs must be different in order to operate

in different intracellular metabolic pathways. If, after a few therapeutic cycles,

a malignant tumor starts to express MDR, this indicates that its response to

chemotherapy is going to be reduced, which indicates a worse prognosis.

There are several groups of transmembrane transport proteins related to

multidrug resistance, four of which are P-glycoprotein (Pgp), multidrug

resistance-related protein (MRP), lung resistance-related protein (LRP), and

breast cancer related protein (BCRP), all of which are ATP-binding cassette

multidrug transporters.

P-glycoprotein is a transmembrane glycoprotein with a molecular weight

of 170 kDa, encoded by the MDR1 gene, located on chromosome 7 (7q21.1),

which has 12 transmembrane domains and two ATP binding sites. P-

glycoprotein acts as an ATP-dependent membrane efﬂux transporter that

pumps cationic and lipophilic drugs out of cells and so dramatically reduces

their intracellular accumulation. This extrusion mechanism confers resistance

on a large number of cytotoxic drugs, such as anthracyclines, vinca alkaloids,

epipodophyllotoxins, and taxanes, which are not related either structurally or

functionally. In addition to Pgp being present in oncology tissues after cyto-

toxic drug exposure, it is also found in a variety of normal tissues including

the adrenal cortex, the intestinal mucosa, the gastrointestinal epithelium,

294 Nuclear Medicine Physics

the biliary canalicular surface of hepatocytes, pancreatic duct cells, proxi-

mal tubule cells in kidney, myocytes, capillary endothelial cells of the brain

and testes, the uterus during pregnancy, and stem cells from bone marrow

positive for CD34 [182,183].

The presence of Pgp in normal cells acts as a protection mechanism, as

lipophilic and cationic molecules, which are toxins, are extruded to outside

the cells. Some malignant tumors overexpress Pgp from the time of initial

diagnosis, even before exposure to any cytotoxic drug. This overexpression

limits the effectiveness of a wide variety of chemotherapeutic agents such as

daunorubicin, vincristine, ectoposide, and adriamycin, which are substrates

for their activity.

Another transmembrane transport protein, also belonging to the super-

family of ABC transporters, is MRP. It is encoded in humans by several closely

related genes located on chromosome 16 (16p13.1). This protein has a molecu-

lar weight of 190 kDa, has 17 transmembrane domains with two ATP binding

sites, transports lipophilic and anionic drugs, and is expressed in almost

all normal epithelial cells. The MRP transports several noncytotoxic drugs

such as anionic compounds and leukotrienes (LT) (in particular LTC4, LTD4,

and LTE4) and cytotoxic drugs such as vinca alkaloids, epipodophyllotox-

ins, anthracyclines, and camptothecins, most of which are also substrates for

Pgp. Therefore, both the Pgp and the MRP may be overexpressed at the same

time in drug-resistant cells, which also limits the effectiveness of a number of

cytotoxic drugs such as doxorubicin, epirubicine, ectoposide, methotrexate,

cisplatin, vincristine, vinorelbine, and mitoxanthrone, because they function

as their substrates [180,182].

Owing to this behavior, both the Pgp and the MRP are now considered

as major targets for pharmacological intervention. As a result, chemosensi-

tizer molecules able to interact with the referred transporters were developed

which can make the tumors that express Pgp or MRP sensitive to several

cytotoxic drugs.

The action of these modulating molecules or chemosensitizers of MDR is to

block the transmembrane efﬂux proteins, especially Pgp, and so to increase

the intratumor concentrations of cytotoxic drugs.

Over the last few years, several molecules have been used as MDR modula-

tors. The ﬁrst generation of modulators includes molecules such as verapamil,

azidopin, cyclosporin A, and FK506, which act by binding to Pgp, com-

peting with cytotoxic drugs, and are themselves transported by membrane

transporters. The clinical utility of such molecules is, however, very lim-

ited due to their adverse effects, as to have an MDR modulation effect their

concentrations must be very high.

The second generation of modulators includes molecules such as dex-

verapamil, tamoxifen, progesterone, GF120918, and PSC833. These molecules

compete for binding sites, which inhibits the transport of cytotoxic agents, but

theyarenot transported. These modulators aremorepotent and lesstoxic than

the ﬁrst-generation ones. One of the most promising modulators of the second

Imaging Methodologies 295

generation is PSC833. This modulator is a derivative of cyclosporine but lacks

its immunosuppressive effects and its nephrotoxicity. Results obtained in pre-

clinical tests and clinical trials showed that it is a powerful MDR modulator.

However, these tests also showed that it was toxic to the central nervous sys-

tem (CNS), that it was a substrate for Pg, and it is currently considered as a

partial antagonist [182,184].

The third-generation modulators include molecules such as tariquidar and

zozuquidar and were developed to overcome the limitations of the second-

generation modulators. Studies have shown that they are able to speciﬁcally

inhibit Pgp.

With regard to the assessment of MDR, NM has some tracers that were

originally developed for studies on myocardial perfusion. These tracers

are lipophilic and monocationic molecules, labeled with

99m

Tc, a s

99m

Tc-

hexakis(2-methoxyisobutylisonitrile)(

99m

Tc-MIBI),

99m

Tc-tetrofosmin(

99m

Tc-

TF), and

99m

Tc-furifosmin (

99m

Tc-FUR), which are currently in use to assess

the in vivo expression of MDR by tumors.

The MIBI is an isonitrile derivative, whereas tetrofosmin is a diphosphine

derivative. These two molecules are substrates for both Pgp and MRP at

picomolar concentration, and either can be used as a tracer to evaluate resis-

tance to cytotoxic drugs or to give information about resistance reversal if the

patient has been previously treated with an MDR modulator.

The initial uptake and concentrations of the tracers referred to earlier are

due to nonspeciﬁc factors such as perfusion and electrostatic interactions in

the mitochondrial membrane; whereas in the tumor, efﬂux kinetics reﬂect

the level of expression of MDR1 or other similar genes that confer resistance

to multiple drugs. An assessment of the Pgp activity level can predict the

response to chemotherapy or indicate the need of adjuvant therapy with Pgp

inhibitors such as verapamil or cyclosporine, or even with the newer agents

such as PSC833, GF120918, VX-710, tariquidar, or zozuquidar [181,184].

The usefulness of chemosensitizers to reversing Pgp function and, thereby,

increasingtheintracellular accumulation of cationictracers labeled with

99m

has not been well studied. In fact, most studies about the capacity of the two

lipophilic and cationic agents to recognize MDR expression, or its reversal

through the use of modulators, were performed in vitro [184].

In addition to these tracers used in NM by single photon emitters, several

molecules have been proposed to be labeled with positron emitters. These

include the colchicine labeled with

C-colchicine), verapamil labeled

with

C-verapamil), daunorubicin labeled with

C-daunorubicin),

and N-acetyl-leukotriene E4 labeled with

C-LTE4) [180].

6.4.12 Tumor Receptors

Among the characteristics of malignant transformation are the expression of

a large number of membrane receptors and the emergence of new ones.

296 Nuclear Medicine Physics

6.4.12.1 Folic Acid Receptors

Folic acid (FA) receptors of the membrane mediate the intracellular accumu-

lation of FA and its analogs, such as methotrexate. Their expression is limited

in normal tissues, but receptors are overexpressed in several types of tumor

cells. Using ethylenedicystein as a chelator, the FA can be labeled with

99m

(

99m

Tc-EC-FA). This tracer can be used to obtain images that reﬂect the cellular

uptake and consequent intracellular accumulation [185].

6.4.12.2 Sigma Receptors

Although the biology of sigma opioid receptors is not yet fully understood,

its expression has been detected outside the CNS in a large variety of tissues

including the heart, kidneys, adrenal glands, gonads, gastrointestinal tract,

liver, and spleen.

Interms of location, these receptorscan be foundin the plasmamembrane of

some cellular organelles, such as the Golgi complex, endoplasmic reticulum,

and nucleus, where they may be also associated with G-proteins. Two sub-

types are described, the sigma-1 and sigma-2, both expressed in some types of

tumor. The sigma-1 receptorsaremainly expressedin prostate tumor,whereas

the sigma-2 receptors areoverexpressedin melanomas, breastcancer, prostate

cancer, and small cell lung cancer. With regard to these receptors, the higher

the sigma-2 receptors’ expression by a tumor, the greater the degree of pro-

liferation of tumor cells. In some cases of breast cancer, their overexpression

can be so intense that each cell can express more than a million copies of the

receptor.

According to studies performed in cells of breast adenocarcinoma, a

speciﬁc complex of

99m

Tc for the sigma-2 receptors has been recently

synthesized, [N-[2-((3



-N



-propyl-[3,3,1]azabicyclononan-α3-yl)(2-methoxy-

5-methyl-phenylcarbamate)(2-mercaptoethyl)amino)acetyl]-2-aminoethane-

thiolato]Tc(V)oxide) [186–188].

6.4.12.3 Breast Cancer Receptors

Hormonal therapy in breast tumors has been well established for a number of

years, because more than a half of primary breast tumors express receptors for

estrogen and progesterone. For tumors that express receptors, the stimulation

with estrogen has a pro-proliferative effect.

Tamoxifen and raloxifene are selective estrogen receptor modulators that

act as agonists in some tissues such as cardiovasculartissue and as antagonists

in other tissues such as the breast and breast cancers [189].

With this type of distribution in mind, estrogen blocking action is associated

with the slowdown of tumor growth, increasing the survival time, and lower

incidence in patients who undergo prophylactic therapy.

Imaging Methodologies 297

This type of correlation is in the basis of the use of estrogen analogs

labeled with radioactive isotopes to assess the expression of estrogen recep-

tors and to monitor the antiestrogen therapy response in patients with breast

cancers.

The HER-2/neu is a tyrosine kinase transmembrane receptor that is over-

expressed in many of the primary breast cancers, and it is associated with a

poor prognosis. However, its expression is also a predictive sign of response

to adjuvant treatment with doxorubicin. Nevertheless, if the patient has

undergone neoadjuvant therapy with tamoxifen or anthracyclines, the over-

expression of HER-2/neu receptor predicts a poor response to therapy

[189].

When overexpressed, this receptor is an important therapeutic target in

breast cancers. With this goal, therefore, a monoclonal antibody that binds

to the extracellular portion of HER-2/neu, trastuzumab (Herceptin

) was

developed. The use of this molecule improves the therapeutic response by

acting as an adjuvant to ﬁrst-line chemotherapy, particularly in tumors that

overexpress HER-2/neu receptor.

This receptor was achieved by developing monoclonal antibodies anti-

HER-2/neu labeled with

131

I and

111

In. The uptake of these labeled antibodies

by the tumor and its visualization are a sign that can predict the response to

immunotherapy with trastuzumab.

6.4.12.4 Cholecystokinin-B/Gastrin Receptors

The receptorof cholecystokinin-B (CCK-B) or gastrin is expressedin almost all

the telencephalon and in the stomach and is not found in any organ in normal

conditions. It may be overexpressed, however, in human pancreatic, gastric,

and colorectal carcinomas; small cell lung cancer; ovarian stromal tumors;

and astrocytomas. In the thyroid, more than 90% of medullary carcinomas

express this receptor, and the injection of cold pentagastrin has been widely

used as a provocative test for detection of primary, recurrent, or metastatic

medullary thyroid carcinoma [190].

In terms of NM, gastrin heptadecapeptide labeled with

131

I is taken up by

medullary thyroid carcinomas, thus allowing its use in the ﬁeld of metabolic

radiotherapy and in imaging. The uptake of this complex by medullary

thyroid carcinomas reﬂects the receptor’s overexpression [191].

6.4.12.5 Other Receptors

Besides the receptors already mentioned, tumors may overexpress receptors

for other peptides and other small molecules, such as G-protein receptors,

tyrosine kinase receptors, and nontyrosine kinase receptors.

Gastrin releasing peptide receptors, vasoactive intestinal peptide (VIP)

receptors, and type-2 somatostatin receptors are examples of protein-G