Characterizing Individual Tumor Biology

Malignant tumors differ from benign lesions in several regards, notably in having a more active recruitment of neovascularity. This acceleration of angiogenesis is essential for the exponential growth and metastasis of the tumor cells (Folkman 1992). Tumor vessels differ from normal tissue vessels by their structural irregularity (abnormal endothelial cell contours and peculiar branching patterns), heterogeneity (flow, diameter, and spacing), and leakiness to macromo-lecular solutes (Jain 1988; Less et al. 1991; Baish and Jain 2000; EberHard et al. 2000). Recent data from scanning electron microscopy (EM) show that tumor endothelial cells overlap one another and are loosely interconnected, leaving gaps ranging from 0.3 to 4.7 |im (Fig. 3.2) (McDonald and Foss 2000; Hasmzume et al. 2000). These gaps likely account for the macromolecular hyperpermeability that leads to extravasation of plasma proteins, considered necessary for angiogenesis, as well as transendothelial passage of tumor cells, required for hematogenous metastases (Heuser and Miller 1986; Dvorak et al. 1988; Hasmzume et al. 2000).

This endothelial characteristic of macromolecu-lar hyperpermeability in malignant tumors can be exploited by the use of dynamic contrast-enhanced imaging to identify and grade the abnormal tumor microvessels. Stated in the simplest of terms, malignant tumors should leak macromolecular contrast media and benign tumors should not leak.

In clinical oncology, a neoplastic lesion is usually evaluated for its aggressiveness by performing a biopsy followed by histopathologic microscopic examination. However, this method is invasive and can only sample a small percentage of the entire lesion, possibly missing the most aggressive part of the tumor and leading to an erroneous evaluation.

Non-invasive imaging can complement the his-topathologic information and may in some respects surpass it as a means to grade tumor properties. Imaging can be performed on living tissues, on multiple occasions, allows for evaluation of the entire (and often heterogeneous) tumor, and provides both morphologic and physiologic data.

Biopsy tumor specimens are graded by their specific histopathologic characteristics. In breast tumors, for example, the Scarff-Bloom-Richardson (SBR) grading method is used to define the presence and degree of malignant characteristics for a tumor (Bloom and Richardson 1957; Scarff and Tononi 1968). The SBR score sums the microscopic evaluations of three separate morphologic elements: frequency of mitotic figures, nuclear polymorphism, and glandular/tubular formation, each scored from ' 1' to '3'. Benign tumors, were they scored like the malignant lesions, would have an SBR score of '3' (summing the minimum score of '1' in each category), whereas malignant tumors can have scores ranging from '3' to '9'.

In a rodent model of mammary tumors induced by the single intraperitoneal administration of a chemical carcinogen, N-ethyl-N-nitrosourea (ENU), a spectrum of tumors develop over months, paralleling the spectrum of breast tumors encountered clinically in women. Several research groups have used this ENU model to evaluate and compare different contrast media for DCE MRI in the characterization of mammary neoplasms (Daldrup et al. 1998a; Su et al. 1998; Helbich et al. 2000; Turetscmk et al. 2001a).

Daldrup and coworkers (1998a) used this model to determine if DCE MRI enhanced with either an MMCM [albumin-(Gd-DTPA)35] or an SMCM (gado-pentetate dimeglumine) could differentiate benign from malignant tumors, and furthermore, if MRI results could predict the histopathologic SBR score. MRI-assayed microvascular parameters including the coefficient of endothelial permeability, defined as Ktrans (reflecting leakiness), and the fractional plasma

Fig. 3.2a-c. a Scanning electron micrograph of vascular endothelial cells from a mouse mammary tumor, showing irregular cell structure such as cellular overlap, bridges (arrowheads), tunnels, and wide openings in the vessel wall (scale bar represents 15 pm). b Transmission electron micrograph of a mouse mammary tumor blood vessels showing transcellular fenestrae (arrowheads) of 50-80 nm in diameter visible in the endothelial cell (scale bar represents 0.5 pm). c Transmission electron microscopy of mammary tumor endothelium lining showing intercellular gaps, which may account for the characteristic leakiness of tumor blood vessels (scale bar represents 3 pm). (All images courtesy of Donald M. McDonald).

Fig. 3.2a-c. a Scanning electron micrograph of vascular endothelial cells from a mouse mammary tumor, showing irregular cell structure such as cellular overlap, bridges (arrowheads), tunnels, and wide openings in the vessel wall (scale bar represents 15 pm). b Transmission electron micrograph of a mouse mammary tumor blood vessels showing transcellular fenestrae (arrowheads) of 50-80 nm in diameter visible in the endothelial cell (scale bar represents 0.5 pm). c Transmission electron microscopy of mammary tumor endothelium lining showing intercellular gaps, which may account for the characteristic leakiness of tumor blood vessels (scale bar represents 3 pm). (All images courtesy of Donald M. McDonald).

volume, fPV, (reflecting richness of vascularity), were estimated in each tumor for each contrast agent using a simple two compartment tissue model comprising the blood and interstitial water of the tumor tissue. Correlations were sought between MRI-assayed characteristics and pathologic status including assignment to benign or malignant status and SBR scores. MRI-assayed permeability (Ktrans) estimated using the mac-romolecular albumin-(Gd-DTPA)35, showed a significant difference between benign fibroadenomas and malignant carcinomas (p<0.05). All ten benign tumors had Ktrans values of zero, whereas all tumors showing measurable permeability to this macromolecular contrast agent, (Ktrans>0), were diagnosed pathologically as carcinomas. There was a slight overlap in pathology for tumors having no measurable MRI leakiness to macromolecules; other than the ten benign tumors, five of 23 carcinomas had no MRI measurable macro-molecular permeability, but these five tumors also had the lowest possible SBR scores ('3'-'4'). In this series of 33 tumors, a positive MRI-assayed endothelial permeability value, as estimated with macromolecular albu-min-(Gd-DTPA)35, was a consistent sign of malignancy with an observed specificity of 100%. Regarding MRI tumor grading, microvascular permeability to albu-min-(Gd-DTPA)35 (Ktrans) showed a strong positive correlation with histological tumor grade (r2=0.76; p<0.001) (Fig. 3.3).

By comparison, in the same tumors, when using gadopentetate dimeglumine as the contrast agent, there was a broad overlap and no significant difference in Ktrans values observed between benign fibroadenomas and carcinomas (Ktrans of 13.2 versus 13.3, respectively; p>0.99). No correlation between gadopentetate-assayed Ktrans or fractional plasma volume and histologic SBR grade was found (r2=0.01 and p>0.95 for Ktrans; r2=0.03 and p>0.15 for fPV) (Fig. 3.4). This initial report of positive results using macromolecular contrast media and DCE MRI to characterize and grade ENU-induced mammary tumors was reconfirmed in multiple studies despite sometimes differing methods of kinetic analysis, but all using albumin-(Gd-DTPA)x (Su et al. 1998; Turetschek et al. 2001a,b).

The same chemically induced mammary tumor model has been used to evaluate other BPCM for-

Macromolecular contrast agent (Albumin-Gd-DTPA)30

Macromolecular contrast agent (Albumin-Gd-DTPA)30

(Endothelial transfer coefficient) pl/h/cm3 02

Histologic SBR score

Fig. 3.3. Plot showing strong positive and significant correlation between the endothelial transfer coefficient (KPS=Ktrans) after intravenous injection of albumin-(Gd-DTPA)35 and histologic tumor grade in benign (circle) and malignant tumors (triangle). (Adapted from DaLdrup et al. 1998a)

(Endothelial transfer coefficient) pl/h/cm3 02

Histologic SBR score

Fig. 3.3. Plot showing strong positive and significant correlation between the endothelial transfer coefficient (KPS=Ktrans) after intravenous injection of albumin-(Gd-DTPA)35 and histologic tumor grade in benign (circle) and malignant tumors (triangle). (Adapted from DaLdrup et al. 1998a)

Small molecular agent (Gadopentetate)

Small molecular agent (Gadopentetate)

(Endothelial transfer coefficient) pl/h/cm3)

23456789 10

Histologic SBR score

Fig. 3.4. Plot showing the lack of correlation between the endothelial transfer coefficient (KPS=Ktrans) after intravenous injection of gadopentetate, and histologic tumor grade quantified according to the Scarff-Bloom-Richardson method in benign (circle) and malignant tumors (triangle). (Adapted from DaLdrup et al. 1998a)

(Endothelial transfer coefficient) pl/h/cm3)

23456789 10

Histologic SBR score

Fig. 3.4. Plot showing the lack of correlation between the endothelial transfer coefficient (KPS=Ktrans) after intravenous injection of gadopentetate, and histologic tumor grade quantified according to the Scarff-Bloom-Richardson method in benign (circle) and malignant tumors (triangle). (Adapted from DaLdrup et al. 1998a)

mulations and provides a useful means to compare performance of different agents. Using Gadomer-17 (Schering AG, Berlin) with an apparent molecular weight of 17.5 kDa, DaLdrup-Lmk and coworkers (2000) showed a significant difference in MRI-esti-mated permeability between benign and malignant tumors. However, apparently due to a high variability within both fibroadenoma (benign) and carcinoma (malignant) groups, there was no significant correlation between Ktrans or fPV, and histopathologic tumor grade. Similarly, Su and colleagues (1998) reported limited specificity when using the intermediately-sized Gadomer-17 being able to differenti ate between high grade and low-grade carcinomas, but not between low-grade carcinomas and benign tumors.

Turetschek and colleagues (2001a) evaluated MS-325, a small molecule that spontaneously associates with albumin, for characterization of tumor microvessels assaying plasma volume and permeability in the ENU rodent tumor model. No significant correlations were found between MRI-esti-mated characteristics and pathologic tumor grade or microvascular count, a marker of angiogenesis; the lack of correlation was attributed in part to the inability to resolve the kinetics of the small-unbound MS-325 (25% in rats) and the larger protein-bound complex.

Yet another class of potential BPCM, the ultrasmall superparamagnetic iron oxide (USPIO) particles, has been evaluated in the ENU-induced mammary tumor model (Turetschek et al. 2001d). NC100150 injection (Clariscan, Amersham, UK) yielded a strongly positive correlation between MRI-derived Ktrans estimates and histological SBR tumor grade (r=0.82; p<0.001). Ktrans also correlated significantly with histologically assessed microvascular density (MVD). In this study of 19 total tumors, five were benign fibroadenomas, all with non-measurable (zero) leakiness to the USPIO. Nine of 14 carcinomas did show measurable permeability to the MRI probe; the other five carcinomas without leakiness showed low aggressive potential as reflected in low SBR scores. Overall, the tumors that were leaky to USPIO were all carcinomas. The significance of these results in animal tumor models is accentuated because USPIO particles have already been tested extensively in human clinical trials as angiographic and lymph node enhancers with favorable results; governmental approval for USPIO is anticipated soon (Kernstine et al. 1999; Hudgins et al. 2002; Varanyay et al. 2002).

A preliminary study was performed in women to evaluate the capacity of USPIO particles for breast tumor characterization. Although the qualitative tumor enhancement evident to the eye was relatively low with the USPIO at a dose of 2 mg Fe/kg, making tumor detection more difficult than with gadopen-tetate, Daldrup-Link and colleagues (2002) found a significant difference in enhancement patterns and kinetic analyses between carcinomas (n=9), and benign lesions including fibroadenomas and mastopathic lesions (n=10) (Daldrup-Link et al. 2002). However, there was no significant difference in enhancement profiles between these same two groups using the small-molecular gadopentetate. The lack of significance was attributed to the broad overlap in gadopentetate enhancement patterns between the two groups, results similar to those observed in the animal mammary models. The results of this clinical study in women with breast tumors supports a unique role of blood pool contrast media for tumor characterization, allowing the differentiation of benign from malignant lesions. Initial tumor detection may be best accomplished by other means such as radiographic mammography or SMCM-enhanced MRI.

MMCM-enhanced MRI can also non-invasively assay tumor angiogenesis, the process by which cancers recruit new vessels growing in from the nontumor host tissue. Although there is no single "gold standard" assay for angiogenesis, the counting of immunohistochemically stained endothelial cell clusters within a given area of the tumor to yield the microvascular density (MVD) has been used widely as a surrogate marker of the angiogenesis process (Weidner 1995). Clinical series have shown that MVD correlates with the presence of metastases at time of diagnosis and with decreased patient survival in numerous types of malignancies including breast, lung, prostate, bladder, ovary, and head and neck carcinomas. Of note, the status of tumor cell differentiation, for example, the SBR score, and that of concomitant tumor angiogenesis do not necessarily correlate. In fact, tumor grade and angiogenesis are considered independent biological characteristics.

Using albumin-(Gd-DTPA)35 in two groups of xenograft human breast carcinomas grown in athy-mic rats, van Dijke and coworkers (1996) evaluated the potential of MMCM-enhanced MRI to assay angiogenesis. The first group of tumors was angio-genically less active and showed a slower growth rate with distinctly and significantly lower MVD values (MVD<50; p<0.001). In contrast, the more aggressive and rapidly growing group of tumors had MVD values ranging from 80 to 305. MRI-derived tumor plasma volumes and permeability estimates increased exponentially with increasing microvascular density, and there was a strong positive correlation between MRI-assayed microvascular characteristics and MVD (r2=0.8; p<0.001) (Fig. 3.5).

The authors discussed that MRI estimated angiogenesis might be superior to the pathologic MVD assay, which reflects only the number of vessels, because the MRI technique reflects both vessel number and size through the plasma volume assay, and the functional characteristics of the vessels through the permeability essay. Indeed, MRI samples the entire tumor, is non-invasive, is not operator-dependent, and can be used repeatedly in the same subject.

Microvascular Density (MVD)

Fig. 3.5. Correlation between MRI-assayed permeability (KPS=Ktrans) and pathologically determined microvascular density in two populations of xenograft breast tumors, a slow-growing group (circles) and a more aggressive rapidly-growing group (triangles). (Adapted from van Dijke et al. 1996)

Microvascular Density (MVD)

Fig. 3.5. Correlation between MRI-assayed permeability (KPS=Ktrans) and pathologically determined microvascular density in two populations of xenograft breast tumors, a slow-growing group (circles) and a more aggressive rapidly-growing group (triangles). (Adapted from van Dijke et al. 1996)

Monitoring Tumor Response to Treatment

Beyond assessing individual tumor biology at time of diagnosis, MMCM-enhanced MRI with quantitative estimates of microvascular blood volume and permeability have been shown effective to define the responses of individual tumors to various forms of treatment. In this sense, MMCM-derived MRI measurements are treatment response biomarkers.

In current clinical practice, monitoring of tumor treatment response is typically assessed on imaging examinations by the measurement of tumor size. Generally such size evaluations are performed at 6-or 8-week intervals. Adding to the problem of a long delay, tumor size is a rather indirect and imprecise morphologic sign of treatment effectiveness. Defining additional and more direct biological signs of response to treatment would be highly desirable, particularly if that response were detectable non-inva-sively and before other measurable changes such as tumor shrinkage or necrosis. However, not only do clinicians need a means to define biological effectiveness soon after the initiation of a given treatment, there is also an urgent requirement in the field of oncologic pharmaceutical development for a sensitive treatment response marker for a broad spectrum of therapeutic agents undergoing development.

The need for MRI treatment biomarkers is in no place more evident than for angiogenesis inhibitors. This class of anti-cancer drugs is known to generally retard tumor growth, but not to cure or totally eradicate lesions; therefore, the drug may be effective but the tumor persists, albeit inhibited from attracting additional blood vessels (Fenton et al. 2001). An imaging biomarker may be superior to tumor sizing for documentation of angiogenesis inhibitory effect. These biomarker changes may be detectable hours after treatment initiation, rather than in weeks or months needed typically to define substantial changes in tumor size. An early evaluation of therapeutic efficacy would allow physicians to adapt treatment regimens and doses based on individual response, optimally associate anti-angiogenic with other anti-tumor therapies, and interrupt an eventually inefficient treatment, reducing morbidity.

Several reports indicate that MMCM-enhanced MRI-derived microvascular characteristics can be used effectively to monitor the biological effectiveness of angiogenesis inhibitory treatment (Cohen et al. 1995; Schwickert et al. 1996; Pham et al. 1998; Su et al. 1999; Gossmann et al. 2000; CLement et al. 2001; Roberts et al. 2001, 2002; Turetschek et al. 2001c; Anegrmi et al. 2002; Gossmann et al. 2002; Petrovsky et al. 2002). Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) is considered a central signaling molecule in the complex process of tumor angiogenesis (Dvorak 2000). VEGF/VPF has multiple stimulatory effects, all tied to angiogenesis, including endothelial cell mitogenesis, endothelial cell migration, cell survival, and increased endothelial permeability. The VEGF-induced hyperpermeability of cancer microvessels, 50,000 times stronger than that induced by histamine, leads to an extravasation of macromo-lecular proteins that form a favorable substrate in the tumor interstitium into which the new vessels grow. It was therefore relevant to design an experiment which would probe the potential of MRI-assayed microvascular responses for the detection of anti-angiogenic effect in tumors.

The first anti-angiogenic drug tested in our center was a human antibody directed against VEGF (Avastin, Genentech, South San Francisco, CA) (Pham et al. 1998). A significant (p<0.01) suppression (>75%) of MRI-assayed microvascular hyperpermeability, expressed as the coefficient of permeability surface area product (Ktrans), was observed in a human breast cancer (MB-MDA-435) grown in athymic rats following a 1-week course of three 1-mg doses of human anti-VEGF antibody. With appropriate controls, the anti-VEGF antibody was shown to reduce tumor weight, growth rate (Fig. 3.6), and MRI-assayed permeability to the blood pool contrast agent (Fig. 3.7).

In a follow-up experiment (Brasch et al. 2000), MMCM-enhanced MRI demonstrated a reduction in permeability, induced by anti-VEGF antibody as early as 24 h after only a single dose. A significant (p<0.01) reduction in tumor microvascular macromolecular permeability to levels less than 40% of baseline was recorded.

In a parallel manner, subsequent studies showed anti-VEGF antibody induced reductions in MRI-assayed permeabilities in models of human ovarian carcinoma and cerebral glioblastoma multiforme (Gossmann et al. 2000, 2002). In the case of intraperitoneal human ovarian cancers (SKOV-3) grown in athymic rats, after five 1-mg doses of anti-VEGF antibody administered every 3 days, permeability assayed by MMCM-enhanced MRI was seen to decrease significantly in treated tumors, while saline-treated control ovarian tumors exhibited an increase in permeability to MMCM (Fig. 3.8).

Consistent with the hypothesis that elaboration and deposition of VEGF/VPF by ovarian cancer cells into the peritoneal cavity leads to microvascular hyperpermeability, macromolecular extravasation,

Tumor Volume 4000 " (mm3)

Anti-VEGF treated

Number of days after tumor inoculation

Fig. 3.6. Tumor growth for controls and animals treated with 1-mg doses of anti-VEGF antibody every third day over a period of 1 week. Notice the substantial slowing of tumor growth in the anti-VEGF antibody-treated group. (Adapted from Pham et al. 1998)

Anti-VEGF treated

Number of days after tumor inoculation

Fig. 3.6. Tumor growth for controls and animals treated with 1-mg doses of anti-VEGF antibody every third day over a period of 1 week. Notice the substantial slowing of tumor growth in the anti-VEGF antibody-treated group. (Adapted from Pham et al. 1998)

control anti-VEGF

control anti-VEGF

Permeability Surface Factor (PS) |jl/cm3 • h

Whole Rim Center

Tumor Region of Interest

Fig. 3.7. MRI-assayed permeability for controls (inactive immunoglobin) and animals treated with anti-VEGF antibody following a 1-week course of treatment. Notice a significant reduction in MRI-estimated PS whether assayed for the whole tumor or exclusively in the tumor rim or center. (Adapted from Pham et al. 1998)

Permeability Surface Factor (PS) |jl/cm3 • h

Whole Rim Center

Tumor Region of Interest

Fig. 3.7. MRI-assayed permeability for controls (inactive immunoglobin) and animals treated with anti-VEGF antibody following a 1-week course of treatment. Notice a significant reduction in MRI-estimated PS whether assayed for the whole tumor or exclusively in the tumor rim or center. (Adapted from Pham et al. 1998)

Fig. 3.8. Mean coefficients of endothelial transport in human ovarian carcinomas implanted in nude rats, estimated by dynamic albumin-(Gd-DTPA)35 enhanced MRI, before and after treatment in control animals receiving saline solution and treated animals receiving five 1-mg doses of anti-VEGF antibody every third day. (Adapted from Gossmann et al. 2000)

Fig. 3.8. Mean coefficients of endothelial transport in human ovarian carcinomas implanted in nude rats, estimated by dynamic albumin-(Gd-DTPA)35 enhanced MRI, before and after treatment in control animals receiving saline solution and treated animals receiving five 1-mg doses of anti-VEGF antibody every third day. (Adapted from Gossmann et al. 2000)

and ascites (NAgy et al. 1989), there was a significant reduction in the measured ascites accompanying the reduced permeability in the angiogenically-inhibited tumors (Fig. 3.9).

Other contrast agents have been shown to be potentially useful for the definition of changes in tumor microvessels induced by anti-VEGF antibody treatment. For example, in a human breast cancer rodent model the intermediately sized molecule, gadomer-17, showed significant changes both in permeability (Ktrans) and in fractional blood volume (fPV) after treatment (Roberts et al. 2001). In a similar study, the serum protein-binding molecule B22956/1 also demonstrated a decrease in vascular permeability (Ktrans) reflecting the biological effectiveness of the antibody on tumor vessels (Roberts et al. 2002).

Dynamic MMCM-enhanced MRI has examined other anti-angiogenic drugs known to diminish tumor growth and metastatic spread for measurable effects on microvessels. Turetschek and cowork-ers (2001c) studied the effect of an inhibitor of the tyrosine kinase VEGF receptor (PTK787/ZK222584, Novartis, Basel, Switzerland) in athymic rats bearing human MB-MDA-435 breast adenocarcinomas. MRI-assayed microvascular characteristics were evaluated to determine whether they could reflect treatment efficacy, and were compared to tumor size and microvessel density, respectively the clinical and pathological methods used to evaluate biological response. Two macromolecular contrast agents were tested, albumin-(Gd-DTPA)35 and USPIO (SHU555C, Schering AG, Berlin, Germany), to generate quantitative estimates of tumor blood volume and microvas-cular permeability.

With both albumin-(Gd-DTPA)35 and USPIO, a decrease in estimated permeabilities was observed in the treated group after VEGF receptor inhibition, whereas there was an increase in MRI-estimated permeabilities for the control group (Fig. 3.10). These microvascular responses correlated with the observed slowing in the treatment group of tumor growth and with the significantly reduced microvascular density.

Petrovsky and colleagues (2002) tested mac-romolecular contrast-enhanced MRI for detection of vascular changes after treatment with another but similar tyrosine kinase inhibitor. Treated animals received this agent, VEGF-RTKI AG013925 (Pfizer, San Diego, CA) at the dose of 25 mg/kg b.i.d. for 12 days. Using a large polylysine contrast agent, shielded by methoxy polyethylene glycol (MPEG) chains, and labeled with gadolinium chelates, they showed a significant decrease (>50%) in the vascular volume fraction of MV-522 human colon carcinoma

Fig. 3.9. Volume of ascites at necropsy in rodents bearing intraperitoneal human ovarian SKOV-3 carcinomas measured for saline-treated control animals and those receiving five 1-mg doses of anti-VEGF antibody every third day. These differences in volume of ascites corresponded to anti-VEGF antibody-induced reductions in MRI-estimated microvascular permeability. (Adapted from Gossmann et al. 2000)

Fig. 3.9. Volume of ascites at necropsy in rodents bearing intraperitoneal human ovarian SKOV-3 carcinomas measured for saline-treated control animals and those receiving five 1-mg doses of anti-VEGF antibody every third day. These differences in volume of ascites corresponded to anti-VEGF antibody-induced reductions in MRI-estimated microvascular permeability. (Adapted from Gossmann et al. 2000)

Fig. 3.10. Coefficient of endothelial transport (KPS=Ktrans) before and after treatment in control animals receiving saline solution and treated animals receiving two daily doses of 50 mg/kg of tyrosine kinase inhibitor, both by oral gavage for 7 days. (Adapted from TurETschEk et al. 2001c)

xenografts in mice after only three inhibitor doses (1.5 days) of the treatment, predictive of a 2.5-times decrease in tumor volume visible after 2 weeks.

In a similar experiment, yet another tyrosine kinase inhibitor, ZD4190 (AstraZeneca Pharmaceuticals, Macclesfield, UK), was tested on the human PC-3 prostate carcinoma implanted in nude mice. A significant decline (>40%) in MRI-estimated permeability was detected after only two inhibitor doses administered in 24 h, when comparing the treated group and the control group (Clement et al. 2001).

MMCM-assayed microvascular status has been applied with success for monitoring responses to other forms of therapy, in addition to anti-angiogenic drugs, and for other diseases in addition to malignancies. For example, acute and highly significant increases in micro-vascular blood volume and permeability to macromo-lecular albumin-(Gd-DTPA)35 were reported following a single administration of gamma radiation (30 Gy) to a mammary tumor model (Cohen et al. 1995). The diseased tissue response to treatment for conditions as diverse as arthritis (Jiang et al. 2002), spinal cord injury (Philippens et al. 2002), and oxygen-induced pulmonary fibrosis can be monitored by MMCM-enhanced MRI (Brasch et al. 1993).

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