Therapeutic potential of antinuclear ... - Cancer Therapy

Cancer Therapy Vol 1, page 179 

Cancer Therapy Vol 1, 179-190, 2003. 

Therapeutic potential of antinuclear autoantibodies 

in cancer 

Review Article / Hypothesis 

Vladimir P. Torchilin 1* , Leonid Z. Iakoubov 2** , Zeev Estrov 3 

1 Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA; 2 c/o 

Procyon Biopharma, Dorval, Canada; 3 Department of Bioimmunotherapy, The University of Texas M.D.Anderson Cancer 

Center, Houston, TX 

__________________________________________________________________________________ 

*Correspondence: Vladimir Torchilin, Ph.D., D.Sc., Department of Pharmaceutical Sciences, Northeastern University, Mugar Building, 

Room 312, 360 Huntington Avenue, Boston, MA 02115, USA; Tel: 617-373-3206; Fax: 617-373-8886; e-mail: v.torchilin@neu.edu 

** Current address: Chronix Biomedical, Inc., Benicia, CA, USA 

Key Words: cancer immunotherapy, autoimmunity, natural antitumor antibodies, antinuclear autoantibodies, nucleosomes 

Abbreviations: MRD, minimal residual disease; AIDS, aquired immunodeficiency syndrome; NHL, non-Hodgkin’s lymphoma; mAb, 

monoclonal antibody; ANA, antinuclear autoantibody; IgM, immunoglobulin M; IgG, immunoglobulin G; ADDC, antibody-dependent 

cellular cytotoxicity; NK, natural killer; NS - nucleosome; BSA, bovine serum albumin; Kd – dissociation constant. 

Received: 19 August 2003; Accepted: 22 August 2003; electronically published: August 2003 

Summary 

We review the numerous data supporting an anticancer function of certain antinuclear autoantibodies (ANAs). 

Circulating ANAs are well known to accompany certain pathological (autoimmunity) and physiological (aging) 

conditions and can be artificially induced by immunization. The pathogenic role of ANAs in autoimmunity is 

established; but the non-pathogenic ANAs, are generally believed not to possess any functional activity. However, 

important research and clinical data permit to hypothesize a definite connection between cancer and ANAs. The 

idea of inducing autoimmunity as an approach to enhance the immune component in cancer therapy has been 

proposed recently (Pardoll, D 1999, Proc Natl Acad Sci USA 10, 5340-5342). Based on the available data, we 

hypothesize that exogenous ANAs may be used as anticancer therapeutics. Among these ANAs, nucleosome-specific 

ANAs of the aged may be particularly useful since, at least in the aged, they exist as a non-pathogenic moiety, which 

suggests they will have minimal adverse effects when used as anticancer therapeutics. 

I. Introduction 

Natural control over neoplasia 

Studies over the past two decades have revealed the 

presence of neoplastic cells in cancer patients who were 

considered cured or who had attained complete remission 

following successful therapy. Tumor cells detected at a 

level below the resolution of conventional microscopy 

have been termed MRD (reviewed in Moss 1999; Faderl et 

al, 1999, 1999a). When MRD persists asymptomatically 

for years without any increment in tumor mass, the tumor 

is thought to be “dormant” (Uhr et al, 1997). Modern 

sensitive techniques such as flow cytometry, fluorescence 

in situ hybridization, and polymerase chain reaction have 

increased the sensitivity of MRD detection. Molecular 

evidence of residual leukemia cells has been detected in 

the bone marrow for as long as 9 years following 

completion of therapy for acute lymphoblastic leukemia 

(Potter et al, 1993). Low levels of MRD were found in 15 

of 17 acute lymphoblastic leukemia patients who remained 

in complete remission 2-to-35 months after completion of 

all treatments (Roberts et al, 1997). Long-term persistence 

of MRD without clinical relapse has been observed in 

179 

patients who have undergone allogeneic stem cell 

transplantation for chronic myelogenous leukemia and in 

patients with acute myeloid leukemia (Chang et al, 1993; 

Nucifora et al, 1993; Radich et al, 1995; Kenchtli et al, 

1998) and childhood leukemia (Vora et al, 1998), 

suggesting that leukemia cells may survive for more than a 

decade in a dormant state. “Ultra-late” recurrences of solid 

tumors have been described over the years (Tsao et al, 

1997; Karrison et al, 1999). Recent reports on the 

detection of MRD in hematological malignancies such as 

lymphomas as well as in solid tumors (Corradini et al, 

1999; Sharp and Chan, 1999; Gath and Brakenhoff 1999; 

Kvalheim et al, 1999; Maguire et al, 2000) indicate that 

long-lasting MRD is not disease- or tissue-specific. 

The capability to confine tumor cells is not limited to 

the state of MRD. Asymptomatic occult neoplasms such as 

prostate cancer have been detected in elderly patients who 

died of unrelated causes (Gatling 1990), and “diseasespecific” 

fusion gene products including BCR-ABL, BCL2- 

IgH, MLL-AF4, and the partial tandem duplications of 

MLL have been detected in healthy individuals who did 

not develop cancer during the follow-up period (Biernaux 

et al, 1995; Dolken et al, 1996; Uckun et al, 1998). Thus,

Torchilin et al: Therapeutic potential of antinuclear autoantibodies in cancer 

neoplastic cells may remain dormant for years (Faderl et 

al, 1999, 1999a; Estrov and Freedman 1999) while the 

human organism successfully confines them, keeping them 

at a “subclinical” level. For this reason, the benefits of 

therapeutic intervention in patients with MRD remain 

questionable (Faderl et al, 1999, 1999a, 2000; Estrov and 

Freedman 1999). 

Finally, the spontaneous remission of cancer, though 

extremely rare (1 in 60,000 - 140,000 cancer cases) 

(Chang 2000), is a well-established clinical phenomenon 

that provides additional evidence that the human organism 

is capable of combating cancer. Spontaneous remission 

has been reported in leukemia (Bernard and Bessis 1983, 

Paul 1994; Bhatt et al, 1995; Dinulos et al, 1997; Grundy 

et al, 2000), malignant melanoma (Barr 1994) and other 

skin tumors (Barnetson and Halliday 1997), brain tumors 

(Bowles and Perkins 1999), breast cancer (Jena et al, 

2000), lung cancer, and other neoplasms (Kappauf et al, 

1997). This phenomenon is not age-restricted or diseaseor 

tissue-specific. 

What mechanisms does the human organism recruit 

to confine neoplasia, and how can they be used clinically? 

The data on increased tumor frequency in 

immunocompromised hosts indicate that immune 

surveillance plays an important role in tumor growth 

suppression. The sporadic occurrence of both virusdependent 

and -independent opportunistic tumors has been 

reported in immune-deficient patients (Ioachim 1990; 

Filipovich et al, 1994; Penn 2000) such as those who are 

immunosuppressed owing to organ or bone marrow 

transplantation (Penn 1993, Restrepo et al, 1999, Sobecks 

et al, 1999, Swinnen 2000, Kwok and Hunt 2000, Angel et 

al, 2000, Rinaldi et al, 2001, Haagsma et al, 2001, Bhatia 

et al, 2001), severe combined immunodeficiency (McClain 

1997; Elenitoba-Johnson and Jaffe 2001), or AIDS (Fiegal 

1999; White et al, 2001; Frisch et al, 2001). Perhaps the 

most compelling data are from patients with AIDS. The 

incidences of NHL, central nervous system NHL, and 

Hodgkin’s disease are approximately 100-fold, 3000-fold, 

and 10-fold higher in AIDS patients than the incidences in 

the overall population (Straus 2001). Similarly, AIDS 

patients have an increased risk of developing B-cell and Tcell 

lymphomas of all types (Biggar et al, 2001). In 

addition, neoplasms thought not to be immunodeficiencyrelated 

or virally induced, such as carcinomas of the 

rectum, rectosigmoid, trachea, bronchus, lung, skin, 

connective tissues, brain, and central nervous system have 

been found in AIDS patients up to 7 times more frequently 

than in the general population (Gallagher et al, 2000; 

Phelps et al, 2001; Clarke and Glaser 2001). One may 

assume that other, slower growing tumors might remain 

undetected in these patients because of their shortened life 

span. 

Of the two branches of the immune system, cellular 

and humoral, cellular immunity has been investigated 

most extensively and utilized clinically (Pardoll 2001). 

Donor lymphocyte infusion has been utilized to suppress 

tumor cell re-growth in patients treated with marrow or 

blood stem cell transplantation (Appelbaum 2001), and exvivo-expanded 

dendritic cells were successfully used in 

180 

clinical trials in patients with various neoplasms (Baggers 

et al, 2000). Recent success in using certain mAbs as 

anticancer agents has re-attracted investigators’ attention 

to the role of antibodies in antitumor immunity. This 

article reviews the evidence supporting the hypothesis that 

the autonomous production of anticancer antibodies is one 

measure used by the immune system to confine neoplasia 

and that certain ANAs of different etiologies confer the 

humoral branch of antitumor immunity. 

II. Humoral immunity, ANAs, and 

cancer 

A. Autonomously produced antitumor 

antibodies 

It has been well established that natural antitumor 

antibodies may be present in healthy individuals (Colnaghi 

et al,1977, Chow et al, 1981, Colnaghi et al, 1982). The 

data on the potent in vivo suppression of experimental 

tumors by natural antibodies (Kerstin et al, 1996) support 

their possible tumor-preventive role. Normal human serum 

was shown to contain natural IgM antibodies cytotoxic to 

human neuroblastoma cells (Ollert et al, 1996; David et al, 

1999). Preliminary results of a phase I/II clinical trial 

showed an effective arrest of neuroblastoma growth in 

patients who received such antibodies purified from the 

blood of healthy antibody-positive donors (Schmitt et al, 

1999). Nevertheless, influenced by the limited success of 

tumor-specific antibodies against established tumors in 

early clinical trials (Jurcic et al, 1996), most investigators 

remained skeptical about the antineoplastic role of 

humoral immunity in general. Several factors were blamed 

for the limited success of mAb therapy: the shedding of 

the target antigen from the tumor cell surface, the limited 

capability of the antibodies to penetrate bulky tumors (Jain 

1994), the antibodies’ short half-life in the circulation and 

limited delivery to tumor sites, the inadequate recruitment 

of host leukocytes bearing constant (Fc) region receptors, 

the internalization of the target antigens that render the 

neoplastic cell resistance, and the lack of highly specific 

tumor antigens (Schnipper and Strom 2001). 

Recently, mAbs targeting antigens that are not shed 

from the surface of tumor cells were shown to have a 

substantial therapeutic effect: trastuzumab (Herceptin, a 

mAb against HER-2/neu, a protein overexpressed in breast 

cancer cells) against solid tumors, and rituximab (Rituxan, 

a humanized mAb against the B-cell-specific antigen 

CD20) against hematologic malignancies (Agus et al, 

2000; Marshall 2001). The clinical efficacy of these mAbs 

supports an important anticancer role of humoral 

immunity. Natural antibodies might be effective as well, 

particularly in the early stages of tumorigenesis, when 

increased intratumoral interstitial pressure, which prevents 

antibody penetration, does not exist. 

Though little is known about their targets on tumor 

cells (Chow et al, 1981; Aoki et al, 1966; Pierotti and 

Colnaghi 1967; Martin and Martin 1975; Cote et al, 1983), 

most natural anticancer antibodies are tumor type-specific. 

Nevertheless, in recent years, we have identified a subset

of natural antibodies capable of binding to the surface of a 

broad spectrum of cancer cells but not normal cells 

(Iakoubov et al, 1995, 1995a; Iakoubov and Torchilin 

1997, 1998). These antibodies are the natural ANAs, 

which are present in a substantial proportion of healthy 

rodents and humans, especially, aged (Globerson 1993; 

Xavier et al, 1995). 

B. Possible anticancer activity of agerelated 

and age-unrelated ANAs 

Natural autoantibodies are a substantial part of the 

natural antibody repertoire, which is present throughout 

the life span of higher mammals (Cote et al, 1983, Daar 

and Fabre 1981, Guilbert et al, 1982, Dighiero et al, 1983, 

Iakoubov et al, 1988; review in ref. Avrameas 1991). It 

was found that the natural autoantibody repertoire of aged 

mice is drastically different from that of newborns and 

healthy adults (Sakharova et al, 1986; Iakoubov et al, 

1988), with antinuclear specificity being more frequent in 

the aged (Xavier et al, 1995; Iakoubov et al, 1988). Ten of 

11 IgG class monoclonal autoantibodies, derived from the 

splenocytes of healthy aged non-immunized Balb/c mice, 

were shown to possess antinuclear activity, whereas no 

such mAbas could be obtained from newborn or healthy 

adult non-immunized mice. Autoantibodies, such as antithyroglobulin 

antibodies and ANAs, have repeatedly been 

found at significantly higher titers in older humans and 

laboratory animals without overt disease than in younger 

controls (review in refs. Walford 1974, Globerson 1993). 

Although, certain natural antibodies have long been 

suspected to participate in host protection against 

neoplasia (Aoki et al, 1966; Pierotti Colnaghi 1967; 

Martin and Martin 1975; Chow et al, 1981; Cote et al, 

1983), ANAs of the aged were believed just to reflect 

some disregulation in the immune system and were not 

known to have any functional activity (Ben-Yehuda and 

Weksler 1992). The presence of elevated blood levels of 

non-pathogenic ANAs is a characteristic feature of the 

immune system of the aged (Whitaker and Willkens 1966; 

Cammarata et al, 1967; Siegel et al, 1972; Hallgren et al, 

1973; Walford 1974; Wijk 1976; Globerson et al, 1993; 

Xavier et al, 1995). Based on their binding specificity, it 

was hypothesized that ANAs of the aged are an important 

component of the natural autoantibody repertoire and 

participate in antitumor immunosurveillance (Iakoubov 

and Torchilin 1997). 

The hypothesis was also based on other 

considerations. Aging is an established risk factor for 

tumorigenesis. Various immune functions, especially those 

of T lymphocytes, decline with aging (review in ref. Ben- 

Yehuda and Weksler 1992). However, implanted tumors 

grow at a significantly lower rate in aged laboratory 

animals than in younger ones (Weksler et al, 1990). 

Although this difference could be attributed to 

physiological changes caused by aging, such as reduced 

blood flow and a diminished supply of nutrients, certain 

immune tumor-suppressor mechanisms upregulated in the 

aged might compensate for the deterioration of the T-cell 

immune function. Age-related elevation of ANA in 

combination with enhanced ADCC mechanisms in the 


181 

aged (Ziolkowska et al, 1987) might represent such an 

upregulated immune mechanism. 

The hypothesis that certain ANAs of the aged have 

antitumor activity is strongly supported by the results of 

direct in vivo experiments, in which mAb 2C5 

(monoclonal tumor cell surface-reactive ANA of IgG2a 

isotype obtained from non-immunized healthy aged Balb/c 

mouse) effectively suppressed the growth of EL4 T 

lymphoma in young syngeneic C57BL/6 mice and 

prolonged survival time in B16 melanoma-bearing mice 

(Iakoubov et al, 1995, 1995a, Iakoubov and Torchilin 

1997). Data on the tumor reactivity and antitumor 

properties of some ANAs of a different origin 

(autoimmune ANAs and ANAs induced by immunization) 

(Walker and Bole 1976; Johnson and Shin 1983; LeFeber 

et al, 1984; Okudaira et al, 1987; Rekvig et al, 1987; 

Astaldi Ricotti et al, 1987; Jacob et al, 1989; Prabhakar et 

al, 1990; Bachman et al, 1990; Sorace and Johnson 1990; 

Kubota et al, 1990; Bennett et al, 1991; Mecheri et al, 

1992; Klinman 1992; Bouanani et al, 1993; Raz et al, 

1993; review in refs. Brinkman et al, 1990; Jacob and 

Viard 1992) seem to favor the hypothesis. 

Key properties of ANAs formulated in connection 

with systemic autoimmune diseases (Monestier and Kotzin 

1992; Monestier et al, 1993; Casiano and Tan 1996) may 

also be relevant to ANAs’ possible involvement in the 

control of neoplasia. ANAs are directed against certain 

components of functionally important subcellular particles 

(Mohan et al, 1993; Monestier 1997), and frequently target 

autoantigens associated with active cell division and 

proliferation. Casiano and Tan (1996) further stated that 

these properties “support the hypothesis that ANAs are 

driven by subcellular particles such as organelles or 

macromolecular complexes which might be in an activated 

or functional state. This hypothesis leads to the central 

question of how endogenous subcellular particles that are 

normally sequestered can be released from cells and 

exposed to the immune system in a manner that renders 

them capable of driving a sustained ANA response. An 

emerging view is that apoptosis could be a mechanism by 

which potentially immunostimulatory self-antigens might 

be released from cells.” Similar phenomena may take 

place in the development of a pan-specific anticancer 

immune response. 

Certain additional data discussed below, though not 

directly related to ANA of the aged support ANAs 

anticancer properties. Numerous reports provide direct and 

indirect evidence that ANAs unrelated to age may also 

possess antitumor activity. First, supportive data were 

obtained in studies of patients with autoimmune diseases. 

It was found that the mortality rate from cancer in patients 

with autoimmune diseases is noticeably less than that in 

the healthy population (Palo et al, 1977). The proportion 

of cancer-related deaths in patients with multiple sclerosis 

is 67% of that observed in the age-matched general 

population (Sadovnik et al, 1991). Conversely, 

experimental suppression of autoimmune manifestations in 

spontaneously autoimmune mice sharply increases the 

incidence of spontaneous tumors with the most common 

types being carcinomas, pulmonary adenomas, and


lymphomas (Walker and Bole 1976, Russell and Hicks 

1968, Walker et al, 1978, Hahn et al, 1975, Morris et al, 

1976). These data suggest that certain components of the 

immune system characteristic of systemic autoimmunity 

may at the same time have an antitumor function (Walker 

and Bole 1976). An important feature of systemic 

autoimmunity is the presence of ANAs (review in ref. von 

Muhlen and Tan 1995). Although the appearance of 

tumors in immunosuppressed animals may be connected to 

the suppression of various immune mechanisms 

controlling tumors, some autoantibodies from autoimmune 

mice may have the same specificities as autoantibodies 

from the aged (Astaldi et al, 1987; Klinman 1992, 

Bouanani et al, 1993) and may thus be related to tumor 

control. Data from many investigators indicating the 

ability of autoimmune ANAs to react with the cell surface 

(LeFeber et al, 1984; Okudaira et al, 1987; Rekvig et al, 

1987; Jacob et al, 1989; Prabhakar et al, 1990; Bachman et 

al, 1990; Kubota et al, 1990; Bennett et al, 1991; Mecheri 

et al, 1992; Raz et al, 1993; Rekvig and Hannestad 1997; 

Koutouzov et al, 1996; review in refs. Brinkman et al, 

1990; Jacob and Viard 1992) also support such possibility. 

It should be emphasized that most of these investigations 

aimed to study ANAs’ role in autoimmunity and to show 

that ANAs add to the severity of autoimmune disturbances 

owing to their ability to react with the cell surface; no 

special attention was paid to whether there are ANAs that 

can selectively recognize the surface of tumor cells but not 

normal cells. 

Second, ANAs have been described that appear in 

response to immunization. In one study, a mAb that was 

later found to have an antinuclear nature (Sorace and 

Johnson 1990), was generated by active immunization 

with leukemia cells. Treatment with this antibody 

significantly suppressed leukemia cell growth in rats 

engrafted with 10 2 - 10 3 leukemia cells (Johnson and Shin 

1983). The life span of mice bearing Dalton’s lymphoma 

ascites tumor cells was increased by immunization with 

conjugates of guanosine-BSA, GMP-BSA, and tRNA- 

MDSA complex before transplantation of the tumor cells 

(Kala and Antony 1996). In addition, nucleic acid-reactive 

antibodies were shown to inhibit the growth of 

transformed cells in vitro as a result of the higher rate of 

endocytosis in transformed cells. 

Third, a certain positive role of ANAs has been noted 

in some cancer patients. Multiple reports on circulating 

ANAs in patients with malignancies have been recently 

confirmed in patients with lung cancer (Fernandez-Madrid 

et al, 1999, Blaes et al, 2000) and colorectal carcinoma 

(Syrigos et al, 2000), and some of these antibodies were 

associated with a prolonged survival without disease 

progression. Earlier, antibodies against autologous tumor 

cell proteins in patients with small-cell lung cancer were 

shown to be associated with improved survival (Winter et 

al, 1993). 

C. Hypothetical mechanisms of antitumor 

activity of ANAs 

ANAs bind tumor cells, but it is unclear how this 

binding affects the cells. Unconjugated mAbs may 

182 

mediate ADCC, induce complement-mediated lysis, or, in 

some cases, trigger apoptotic cell death. The second and 

third of these mechanisms probably have no significant 

role in the antitumor effect of ANAs. Complementmediated 

lysis, though crucial in bacterial killing, is not 

considered a major mechanism in killing eukaryotic cells 

(Ross 1986). We are also not aware of any ANA able to 

initiate apoptosis, though ANA binding to surface NSs is 

known to induce internalization (Koutouzov et al, 1996). 

The monoclonal ANA 2C5 neither induced complementmediated 

cytotoxicity nor affected the proliferation of EL4 

and S49 T cell lymphoma cells. However, the monoclonal 

ANA 2C5 induced significant ADCC in vitro, especially 

in the presence of exogenous NSs in the culture medium 

(Iakoubov and Torchilin 1997, 1998). That is why ADCC 

may underlie the efficacy of ANAs in vivo, along with the 

ability of ANA-based immune complexes to cause the 

production of immunostimulatory cytokines (Nakoin and 

Ralph 1988). The effectiveness of ADCC is related to the 

isotype of the biologically active Fc part of the 

immunoglobulin molecule. Differences between various 

murine IgG isotypes exist; there is no clear pattern, 

although IgG2a, IgG2b, and IgG3 have been claimed to be 

the most effective (Herlyn et al, 1985). These isotypes 

(especially IgG2a) are much less effective in mediating 

complement-dependent lysis of target cells. Many 

monoclonal ANAs originating from autoimmune mice, as 

well as monoclonal ANAs 2C5 and 1G3 originating from 

healthy aged mice (Iakoubov et al, 1995, Iakoubov and 

Torchilin 1997), belong to the IgG2a isotype. In addition 

to ADCC, the monoclonal ANA 2C5 and similar 

antibodies as well as immune complexes these antibodies 

can form with free chromatin (NSs) in cancer patients’ 

circulation might also enhance cancer immunosurveillance 

by activating some other tumor-specific and non-specific 

immune mechanisms. Routes for such activation vary 

from a well-known phenomenon of immune complexinduced 

release of inflammatory cytokines and proteolytic 

enzymes to recently described toll receptor-involving 

events (Leadbetter et al, 2002) and dendritic cells 

empowerment (Schuurhuis et al, 2002). 

III. ANAs, nucleosomes, and cancer 

A. Tumor cell surface NSs as ANA 

targets 

Some ANAs with anti-DNA or antihistone 

specificity recognize the surface of both tumor cells and 

normal cells (Rekvig and Hannestad 1979, Mecheri et al, 

1992, Raz et al, 1993). An ability to recognize tumor cells 

but not normal cells was found to be characteristic of two 

monoclonal ANAs of the aged with NS-restricted 

specificity; their target was surface-bound NSs (wellcharacterized 

constituents of nuclear material consisting of 

DNA and four pairs of histones arranged in a characteristic 

pattern) (Iakoubov and Torchilin 1997, 1998). One can 

conclude that NSs are specifically associated with tumor 

cells and represent a universal molecular target on their 

surface, whereas free DNA, individual histones, or crossreactive 

determinants are associated with the surface of 

normal cells as well.

Nucleosome binding to the surface of tumor cells 

might be mediated by a 94 kDa protein on the tumor cell 

surface membrane, identified as a NS receptor in the 

human B-lymphoblastoid Raji cell line, monkey CVI cells, 

and rat pancreas islet tumoral cell line RINm (Jacob et al, 

1989). A 50 kDa cell surface NS receptor was also 

recently claimed to be present on the surface of tumor 

cells (Koutouzov et al, 1996); this protein was identified 

as calreticulin by microsequencing (Seddiki et al, 2001). 

Although no nuclear antigens were found on the surface of 

freshly isolated normal blood cells (Emlen et al, 1992), the 

ability of certain normal blood cells to bind NSs in vitro, 

probably via surface DNA receptors, has been 

demonstrated (Bell and Morrison 1991; Hefeneider et al, 

1992). Therefore, the possibility should be considered that 

the absence of NSs from the surface of normal cells may 

be explained by a low concentration of free NSs in the 

normal circulation rather than by the absence of an 

appropriate normal cell surface receptor. At the same time, 

free NSs originating from dead tumor cells are always 

present in spent media of growing tumor cell lines as well 

as in cancer patients (Bell and Morrison 1991; Le Lann et 

al, 1994). They can bind to the surface of DNA- or NSreceptor-bearing 

living tumor cells, which are the first 

cells NSs run into after being released from the dead 

tumor cells in vivo. 

In addition to binding to a chromatin-binding 

receptor on the surface of activated monocytes (Emlen et 

al, 1992), NSs may bind to the surface of activated T cells 

via cell surface proteoglycans, such as heparin sulfate, 

through an electrostatic interaction (usually of low 

affinity) with basic N-terminal residues of NS-forming 

histones (Watson et al, 1999). This finding is in agreement 

with data on the existence of low affinity (Kd 400 nM) 

receptors (in addition to NS-specific high-affinity 

receptors [Kd 7 nM]) on the surface of transformed cells 

(Koutouzov et al, 1996). Recent studies also indicated 

possible involvement of serum amyloid P component in 

chromatin binding (Bickerstaff et al, 1999). Thus, the 

possibility of amyloid P-mediated recognition of NSs by 

scavenging cells exists. 

B. Source of extracellular NSs 

Extracellular NSs are known to be present in 

substantial quantities in tumor cell cultures (Bell and 

Morrison 1991) as well as in patients with tumors (Le 

Lann et al, 1994), where they may originate from 

apoptotic tumor cells, which are present in varying 

quantities in every developing tumor in vivo (Wyllie 

1993). In a dexamethasone-sensitive S49 T cell 

lymphoma, in which the apoptotic death was initiated 

among some of the cells, NSs released from apoptotic 

cells were able to attach to the surface of surviving tumor 

cells, converting them into better targets for ANAs 

(monoclonal ANA 2C5 binding was increased 50-fold) 

(Iakoubov and Torchilin 1998). Nucleosomes appear in 

apoptotic cells as a result of DNA fragmentation by 

endonucleases. It is believed that all the degraded 

intracellular material from an apoptotic cell is endocytosed 


183 

by living neighboring cells or special phagocytes via 

special receptors. However, free extracellular 

nucleochromatin has been observed in vivo under 

conditions accompanied by massive apoptotic death, such 

as lupus erythematosis, AIDS, and cancer (Emlen et al, 

1994; Licht et al, 2001). Although there are clear 

evidences that most of circulating NSs in the blood of 

cancer patients originate from the tumor (Trejo-Becerril et 

al, 2003), the particular molecular mechanisms of NSs 

release from the debris of apoptotic cells are not known. 

C. Practical value of measuring free 

blood NSs 

Although an elevated level of circulating NSs is not 

specific for any benign or malignant disorder, some recent 

data connecting NSs and cancer are of interest. The level 

of plasma NSs was significantly higher (13- to 18-fold) in 

patients with primary breast cancer than in individuals 

without cancer; some other studied cancers also showed 

much increased level of NSs (up to 25-fold) (Kuroi et al, 

2001). The finding that sera of patients with malignant 

tumors contained considerably higher concentrations of 

NSs compared with sera of healthy persons (almost 10fold) 

and patients with benign diseases was also reported 

(Holdenrieder et al, 2001). The concentration of NSs in 

serum was still further increased after chemotherapy or 

radiotherapy. A subsequent decrease in the level of NSs 

often correlated with regression of the tumor (Trejo- 

Becerril et al, 2003; Holdenrieder et al, 2001a). 

D. ANAs and tumor-protective role of 

free NSs. 

Reduced NK activity in neoplastic diseases and other 

disorders characterized by increased (apoptotic?) cell 

death was reported (Moy et al, 1985; Dunlap et al, 1990). 

An immunosuppressive effect of apoptotic cells was 

noticed (Voll et al, 1997) as well as their ability to 

downregulate the antitumor activity of macrophages 

(Reiter et al, 1999). The authors of (Reiter et al, 1999) 

concluded that “given the fact that apoptosis is a 

consequence of various cancer treatment modalities, this 

(macrophage impairment) may lead to a suppression of 

local antitumor reactions and thus actually counteract 

endogenous immune-mediated tumor defence 

mechanisms”. Extracellular chromatin fragments inhibited 

cell killing by NK cells in vitro (Le Lann et al, 1994; Le 

Lann-Terrisse et al, 1997). It is as if release of NSs into 

the extracellular space is a tumor self-defense mechanism 

against NK-mediated lysis. If so, the increased production 

of NS-specific cytotoxic autoantibodies may be considered 

an organism's effort to overcome this tumor mechanism. A 

similar situation has been described in autoimmune 

diseases (Van Bruggen et al, 1999). Data demonstrating a 

prolonged time to disease progression and an increased 

survival rate in cancer patients showing the presence of 

serum ANAs (Palo et al, 1977; Blaes et al, 2000; Syrigos 

et al, 2000) seem to support their possible antitumor 

activity (Figure 1).


Figure 1. Hypothetical mechanism of anticancer activity of ANAs. Based on the currently available data, the following sequence of 

events might be suggested. First, some tumor cells die via the apoptosis and release free nucleosomes (this phenomenon is well 

established). Second, these released nucleosomes (a) attach to the surface surrounding live tumor cells (b, the mechanism or this 

attachment as well as its physiological significance are not completely understood yet), or diffuse into the circulation (c), where some of 

them (d) form complexes with the circulating ANAs (e), the concentration of these complexes being especially high in the tumor 

vasculature. Third, in addition to the formation of immunocomplexes with nucleosomes in the circulation, some ANAs diffuse into the 

tumor and bind (f) nucleosomes exposed on the surface of the live tumor cells. Fourth, freely circulating immunocomplexes (g) attach 

immune effector cells via exposed Fc fragments (h) and make these cells activated. Fifth, as a result of all these phenomena two 

ANA/nucleosome-mediated antitumor mechanisms may begin to work: (I) Tumor cell killing by ANA (probably, mainly via the ADCC, 

though other mechanisms may also be involved); and (II) Tumor attack by various tumor-specific and non-specific immune 

mechanisms, including immune effector cells, activated by locally elevated concentration of ANA/nucleosome immunocomplexes. 

However, the real situation may be more complex since a 

recent study found that both node-negative and nodepositive 

breast cancer patients with high plasma levels of 

NSs had a significantly better relapse-free survival rate 

than patients with low levels of NSs (Kuroi et al, 1999). 

Although plasma concentration of NSs was suggested as a 

new prognostic factor for breast cancer, the cellular and 

biological significance of this observation should be 

further investigated. 

IV. ANAs as potential therapeutic 

agents 

Data accumulated over the past decade indicate that 

the ANAs’ biological role should no longer be considered 

just a pathogenic moiety in autoimmunity (Ben-Yehuda 

and Weksler 1992; Isenberg et al,1994). Circulating ANAs 

are found in about 30% of patients with cancer (Lynn et al, 

1976; Idel et al, 1978; Schattner et al, 1983; Silburn et al, 

1984; Takimoto et al, 1989). Although some of these 

patients develop autoimmune syndromes (review in refs. 

184 

Naschitz et al, 1995; Seda and Alarcon 1995) that 

complicate anticancer therapy and are clinically 

troublesome, the presence of ANAs and autoimmune 

symptoms may be beneficial. For example, patients with 

chronic myelogenous leukemia who develop autoimmune 

phenomena as a result of alpha-interferon therapy attain a 

significantly higher remission rate than those who do not 

(Sacchi et al, 1995). The antitumor function of ANAs is 

the first evidence of a beneficial role of ANAs for the host 

(Iakoubov et al, 1995a; Iakoubov and Torchilin 1997; 

Torchilin et al, 2001). As antitumor agents, certain ANAs 

may have a number of advantages compared with 

conventional antitumor antibodies. First, the ANAs may 

be effective against a broad spectrum of tumors, since they 

appeare reactive against the surface of various tumor cells 

- lymphoid and non-lymphoid, rodent and human. Second, 

side-effects of ANAs may be minimal, since their natural 

presence in the blood is not harmful to the host. Third, the 

underlying antitumor mechanisms may be multimodal and 

hence more efficient. In other words, if certain ANAs are 

found to be effective against a broad spectrum of tumors, 

future optimal treatment regimens may include the

monoclonal ANAs in combination with existing tumor 

type-specific therapies. 

Both clinical and laboratory data indicate that the 

immune system is capable of suppressing neoplastic cell 

growth and certain autoimmune processes are 

accompanied by elevated antitumor potential. Should 

intentional induction of autoimmunity be considered an 

antineoplastic therapeutic strategy (Pardoll 1999), 

especially against the background of observations that 

lupus patients are better protected from cancer (Huges 

2001)? The clinical utilization of certain monoclonal 

ANAs appears to be an attractive option. Since ANAs in 

aged animals are not associated with any known 

abnormality, we can also expect that their application as 

anticancer agents will be not accompanied by adverse 

reactions. A possibility that tumor immunity can be 

uncoupled from autoimmune manifestations was 

demonstrated recently in another experimental system 

(Weber et al, 1998). 

In what setting should ANAs be used? It is possible 

that the full antitumor potential of this type of antibody 

can be realized only in the presence of apoptosis-inducing 

agents that generate the conversion of tumor cell 

chromatin into NSs and release of these NSs into the 

interstitium and binding to the surface of surviving tumor 

cells to make them better targets for the antibodies. As 

with many other antibodies, the ability of ANAs to 

eradicate bulky disease may be limited because of tumor 

penetration problems, their efficacy may lie in fighting 

small metastases and controlling MRD. Still, clinical trials 

is the only way to determine if certain ANAs are effective 

against a broad spectrum of tumors as many experimental 

data suggest. 

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Dr. Vladimir P. Torchilin

Therapeutic potential of antinuclear ... - Cancer Therapy

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