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Clinical Cancer Research Vol. 7, 3186-3192, October 2001
© 2001 American Association for Cancer Research

Regular Articles

Therapeutic Advantage of 90Yttrium- versus 131Iodine-labeled PAM4 Antibody in Experimental Pancreatic Cancer1

Thomas M. Cardillo2, Zhiliang Ying and David V. Gold

The Garden State Cancer Center [T. M. C., D. V. G.], Belleville, New Jersey 07109, and Department of Statistics, Columbia University [Z. Y.] New York, New York 08854


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objectives: Radioimmunotherapy studies using 131I-PAM4 have demonstrated significant antitumor effects in mice bearing human pancreatic cancer xenografts. For several reasons 90Y has been proposed as a more effective radionuclide for radioimmunotherapy of pancreatic cancer. The present study examined whether one radionuclide was more efficacious than the other in tumor-bearing mice.

Methods: Athymic nude mice bearing CaPan1 xenograft tumors (~1.0 cm3) were given increasing doses of either 90Y-PAM4 or 131I-PAM4 up to their respective maximal tolerated doses [MTDs (260 and 700 µCi, respectively)].

Results: 90Y-PAM4 provided significantly greater growth inhibition than the 131I-PAM4 (P < 0.035). Median survival time for the untreated mice was 6 weeks, whereas median survival times for the 131I-treated mice and 90Y-treated mice at their respective MTDs were 17.5 weeks and >26 weeks (the end of the study period), respectively. Within the 131I-PAM4-treated group, two of eight mice were responders (>50% decrease in tumor size) for a median of 14 weeks. At the end of the study (26 weeks), 1 mouse was alive with no sign of tumor. All of the 90Y-PAM4-treated mice were responders with a median duration of response of 20 weeks. Six of the seven mice were alive at week 26, with four mice having no evidence of disease.

Conclusions: These data demonstrate the advantage of 90Y over 131I as the radionuclide for PAM4-targeted radioimmunotherapy of xenografted pancreatic cancer. Furthermore, the duration and extent of the antitumor response suggests that multiple treatment cycles of 90Y-PAM4 may provide an effective therapeutic for the control of pancreatic cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pancreatic cancer is one of the most insidious forms of cancer afflicting adults. The 1999 United States estimates of new cancer cases put pancreatic cancer at 9th and 10th among women and men, respectively. However, it is the fourth leading cause of all cancer deaths in both women and men, surpassed only by lung, colorectal, prostate, and breast cancers. Attributable largely to the location and silent growth of the tumor, most patients present at a time when it is too late to undergo any curative treatment. This has translated into a 5-year survival rate of less than 3% (1) .

Our laboratory has developed MAb3 PAM4 that by immunohistochemistry was found to be reactive with ~85% of pancreatic cancer specimens (2) . Except for a weak reaction with the normal gastrointestinal tract, PAM4 was nonreactive with normal tissues, including the pancreas. In preclinical animal studies, radiolabeled PAM4 targeted to human pancreatic tumor xenografts at high concentrations, demonstrating high specificity (3 , 4) . Experimental RAIT using 131I-labeled PAM4 was carried out in mice bearing s.c. and/or orthotopic human-derived pancreatic tumors. Tumor growth inhibition and long-term survival were significantly greater than for isotype-matched, nonspecific, control and untreated mice. In clinical Phase I trials using the 131I- or 99mTc-labeled PAM4 antibody, scintigraphic evidence of tumors was found in 8 of 10 patients suspected of pancreatic cancer (5 , 6) . Surgery confirmed pancreatic cancer in the 8 patients. One of the two negative patients was found to have chronic pancreatitis and not pancreatic cancer, and the other negative patient had a poorly differentiated pancreatic cancer that was nonreactive with PAM4 by immunohistochemistry.

Currently, 131I is the primary radionuclide chosen for RAIT. The major reasons for this are: (a) the labeling methods for 131I are well defined; (b) it is abundant and inexpensive; and (c) its {gamma} emissions allow for the tracing of in vivo distribution by external camera imaging, and its ß emissions are good for therapy.

Certain physical properties have been proposed for an ideal radionuclide to be used in RAIT (7) . These include a physical half-life (t[1/2]) of 1–3 days, major energy deposition between 0.5 and 30 cell diameters, and single decay-to-ground state. 90Y is a radiometal that fits these criteria and may, thus, be a better choice than 131I for RAIT. 90Y has a greater energy emission than 131I (ß, Emax = 2.27 MeV versus ß, Emax = 0.81 MeV, respectively) and a shorter half-life (t1/2 = 2.67 days versus t1/2 = 8.06 days, respectively). In addition, 90Y will deposit its energy out to 1.81 cm versus only 0.55 cm for 131I (8) . Of particular note, when conjugated to an internalizing antibody, 90Y will be retained within the tumor cell for longer periods of time than will 131I (9, 10, 11, 12) . The residualizing property of radiometals such as 90Y may allow for a higher radiation dose to the tumor than could be achieved by 131I. Considering the potential advantages of using a residualizing radionuclide, we examined the antitumor efficacy of 90Y-labeled DOTA-PAM4 for the treatment of pancreatic cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental Animal Model.
CaPan1, a human pancreatic carcinoma that was obtained as a cell culture from the American Type Culture Collection (Manassas, VA), was established as a solid tumor by s.c. injection of 107 cells into 5-week-old, female athymic nu/nu mice (Taconic, Germantown, NY). Once tumors had grown to ~1 cm3, they were serially propagated by s.c. injection of 0.2 ml of a 20% (w/v) tumor suspension prepared by mincing the tumors in 0.9% saline with subsequent passage through a 40-mesh wire screen. CaPan1 cells produced moderate-to-well-differentiated tumors. Tumors used in this study were passaged <10 times. Animal studies were approved by the Garden State Cancer Center’s Institutional Animal Care and Use Committee and were performed in accordance with the American Association of Laboratory Animal Care (AALAC), United States Department of Agriculture (USDA), and Department of Health and Human Services (DHHS) regulations.

131I- and 125I-Antibody Radiolabeling.
The purification and characterization of cPAM4 has been described previously (2) . Radiolabeling of MAbs with 125I and 131I (NEN Life Science Products, Inc., Boston, MA) was performed by the chloramine-T method (13) . The specific activity of the radiolabeled antibodies was in the range of 9.88–12.3 µCi/µg. Quality assurance was performed as described previously (3) . All of the radiolabeled preparations contained <8% aggregated material and <5% unbound iodine.

90Y- and 111In-Antibody Radiolabeling.
DOTA (Macrocyclics, Inc., Richardson, TX) was conjugated to cPAM4 IgG by a previously described method (14) . 90Yttrium chloride (NEN Life Science Products, Inc., Boston, MA) or 111indium chloride (Iso-Tex Diagnostic, Inc., Friendswood, TX) was added to a reaction vial with DOTA-cPAM4 IgG at a ratio of 5 mCi per mg of cPAM4. The reaction was incubated at 45°C for 15 min and then quenched by removal from the heat source and the addition of 0.1 volume of 100 mM DTPA. This mixture was then incubated at room temperature for 5 min. A volume of 1% human serum albumin in PBS was added to give a final activity concentration of ~1 mCi/ml for 111In-labeled and ~5 mCi/ml for 90Y-labeled DOTA-cPAM4. The specific activity for the 111In label was 5.41 µCi/µg with 1.7% unbound material and less than 1% aggregated material. The specific activity for the 90Y label was 4.49 µCi/µg with 12.9% unbound material and <6% aggregated material. The final labeled antibody product was placed in a dose calibrator (Capintec CRC15R; Ramsey, NJ) and the time and activity recorded.

Biodistribution Studies.
Tumor volumes were determined by caliper measurements in three dimensions and calculated by length x width x depth. Mice bearing tumors of similar size were placed into groups of at least eight animals per time point. Groups of mice received an i.v. injection of a mixture of 125I-cPAM4 (10 µCi) and 111In-DOTA-cPAM4 (25 µCi). The radiolabeled antibody was augmented with unlabeled antibody to ensure that each mouse received a total of 50 µg of antibody. At specific time points, the tumors, as well as various tissues (liver, spleen, kidney, lung, blood, pancreas, and bone), were removed, weighed, and the radioactivity determined in a 2-channel gamma scintillation counter. Data are expressed as %ID/g. Localization indices were calculated by the equation:

Radiation dose estimates were calculated from the biodistribution data. The integral of the time-activity curves was computed trapezoidally with the assumption of no activity at zero time (15) . Student’s t test was used to assess significant differences.

Experimental RAIT.
Mice bearing CaPan1 tumors of ~1 cm3 at the start of the study were used throughout these studies. The MTD of 131I-labeled and 90Y-ITC-Bz-DTPA-labeled cPAM4 IgG were previously determined by i.v. administration of increasing doses of 131I-cPAM4 or increasing doses of 90Y-ITC-Bz-DTPA-labeled cPAM4 (16) . The MTD was defined as that dose of radiolabeled antibody that resulted in all of the mice surviving at least 4 weeks without losing more than 20% of their starting body weight. In mice bearing 1 cm3 CaPan1 tumors, the MTD was found to be 700 µCi for 131I-labeled cPAM4 and 260 µCi for 90Y-labeled cPAM4.

In those experiments comparing 131I versus 90Y RAIT, tumor-bearing mice received either increasing doses of 131I-cPAM4 (350, 525, or 700 µCi) or increasing doses of 90Y-DOTA-cPAM4 (130, 175, 220, or 260 µCi). One group of mice was left untreated as a control. The mice were weighed prior to being injected and then once a week to ensure that their body weight remained more than 80% of starting weight. Measurements for determination of tumor size were likewise performed on a weekly basis.

Data Analysis.
Statistical analyses of tumor growth data were based on AUC and survival time. Profiles of individual tumor growth were obtained through linear and exponential curve modeling. The t test was used to assess the statistical significance between the two MTD treatment groups, as well as to perform other pair-wise comparisons. As a consequence of incompleteness on some of the growth curves (caused by deaths), statistical comparisons of AUC were performed only up to the time at which the first animal within a group was killed. AUC analyses were supported by statistical comparisons of survival data; in this case, survival was defined as time for a tumor to reach 5 cm3. At the termination of the study (26 weeks), some of the animals had not yet experienced the end point, and their observations were considered as censored. The Mantel-Haenszel log-rank test was then used for comparison of treatment arms.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Biodistribution Studies.
Athymic nude mice bearing the CaPan1 human pancreatic carcinoma (~1 cm3 at the start of the study) were given both 25 µCi 111In-DOTA-cPAM4 and 10 µCi 125I-cPAM4. Groups of mice were killed on days 1, 2, 3, 7, and 14. Tissue uptake of radiolabeled antibodies are presented as the %ID/g of tissue (wet weight) in Fig. 1Citation . Tumor uptake of 111In-DOTA-cPAM4 was significantly greater than 125I-cPAM4 at the 2, 3, and 7 day time points (P < 0.0002, 0.0004, and 0.0005, respectively). The highest levels of radiolabeled antibody within the tumor occurred on days 2 and 3, with a 1.67 ± 0.18- and 1.82 ± 0.15-fold higher level of 111In-radiolabeled over 125I-radiolabeled cPAM4, respectively. A steady decline of radioisotope was observed within the tumors after day 3 with an effective t1/2 of 45 h for 111In and 112 h for 125I. Blood clearances were similar for the two isotopes (t1/2 = 22 h and 32 h for 111In and 125I, respectively). Localization ratios (111In:125I) of 1.56 ± 0.19, 1.58 ± 0.29, and 1.81 ± 0.51 for days 2, 3, and 7, respectively, clearly demonstrated the increased tumor uptake and retention of 111In-radiolabeled over 125I-radiolabeled cPAM4. Nontumor tissue uptake and clearance of the radiolabeled antibodies were similar for most tissues except in the liver, spleen, and bone, for which the %ID/g 111In was significantly higher than for 125I. Radiation dose estimates were calculated from the time-activity curves of the biodistribution studies (Table 1)Citation . At their respective MTDs of 260 µCi for 90Y-DOTA-cPAM4 and 700 µCi for 131I-cPAM4 (16) , approximately equal radiation doses would be delivered to the tumors. Tumor:blood radiation dose ratios were 3.27 for 131I-cPAM4 and 4.09 for 90Y-DOTA-cPAM4.



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  		Fig. 1. The biodistribution of coinjected 111In-labeled (25 µCi) and 125I-labeled (10 µCi) cPAM4 in CaPan1 tumor-bearing nude mice. Mice were killed on days 1, 2, 3, 7, and 14, and tissues were collected and counted as described in "Materials and Methods." Tissue: T, tumor; Li, liver; S, spleen; K, kidney; Lu, lung; P, pancreas; Bo, bone; Bl, blood. Bar, SD.

 

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  		Table 1 Radiation dose estimates for 90Y-cPAM4 IgG absorbed dose (cGy) when administered at the MTD

 
RAIT Studies.
Groups of athymic nude mice bearing CaPan1 tumors of ~1 cm3 were given a single cycle of either 90Y-DOTA-cPAM4 (130, 175, 220, or 260 µCi) or 131I-cPAM4 (350, 525, or 700 µCi). Each dose was augmented with unlabeled cPAM4 so that all of the mice received a total of 50 µg of antibody. Overall, the treatments were well tolerated. However, some early deaths did occur with both radionuclides. In the 700-µCi 131I-cPAM4 group, one of nine mice was found dead at week 3. This mouse had a 19% drop in body weight at week 2 versus only 6 ± 6% for the group as a whole, which suggested a therapy-related cause. Although previous studies determined the MTD to be 700 µCi, we may be too close to the toxic level and may need to use a slightly lower dose in the future. Likewise one of eight mice within the 260-µCi 90Y-DOTA-cPAM4 group was found dead at week 3. Although therapy itself cannot be ruled out as the cause of death, the mouse lost only 3% of its body weight at the time of death with a body weight loss of only 3 ± 3% for the group as a whole. The nadir for this treatment group (7 ± 4% weight loss) occurred at day 7. The two mice were excluded from data analyses. The nadir for the 700-µCi 131I-cPAM4-treated group was also reached at day 7 with an 11 ± 4% weight loss. A comparison of weight loss between the two MTD-treated groups approached a significant difference (P < 0.056). Both groups of mice recovered by week 4.

Tumor growth curves were generated with statistical analysis of AUC performed up to the time at which an animal within a group was lost because of disease activity. The 350-, 525-, and 700-µCi 131I-cPAM4-treated groups all had tumors that were significantly smaller than tumors within the untreated group (P < 0.003, 0.015, and 0.003, respectively) at week 3, the last week that data from the untreated group could be compared with the treated groups. There were no significant differences in tumor growth between the different dose levels of 131I-cPAM4 at any of the time points examined. Survival analyses also did not demonstrate any statistically significant differences between the different 131I-treatment groups. However, the 700-µCi group had a longer median survival (17.5 weeks) compared with the 350-µCi (13 weeks)- and 525-µCi (12 weeks)-treated groups (Table 2)Citation .


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  		Table 2 Comparisons of tumor growth inhibition and survival between the various 131I- and 90Y-labeled cPAM4 treatment groups

 
Like the 131I-cPAM4-treated mice, at week 3 all of the 90Y-DOTA-cPAM4-treated mice (130-, 175-, 220-, and 260-µCi groups) had significantly smaller tumors than tumors within the untreated group (P < 0.016, 0.006, 0.006, and 0.004, respectively). Comparisons between 90Y treatment groups showed that administration of 175, 220, or 260 µCi gave significantly greater antitumor activity than did 130 µCi at week 10 (at which time, deaths started to occur in the 130-µCi-treated group; Table 2Citation ). Of particular note, there were no significant differences in tumor growth inhibition between the 175-µCi treatment group and the 220- and 260-µCi treatment groups up to the last assessable time point, week 12, or between the 220- and 260-µCi treatment groups up to week 17. Median survival times for the 175-, 220-, and 260-µCi treatment groups were >=26 weeks (the end of the study).

The tumor growth curves for individual mice within the untreated, the 700-µCi 131I-cPAM4, and the 260-µCi 90Y-DOTA-cPAM4 groups are presented in Fig. 2Citation . At these equitoxic doses, mice treated with 90Y-DOTA-cPAM4 exhibited a significantly greater degree of tumor growth inhibition than mice treated with 131I-cPAM4. At week 11, the last assessable time point for the 131I-cPAM4-treated group, mice had a mean tumor size of 1.64 ± 1.72 cm3 compared with a mean tumor size of 0.20 ± 0.13 cm3 for the mice treated with 90Y-DOTA-cPAM4. This was a significant 8.2-fold difference in tumor size (P < 0.035). Even at the lower 90Y dose of 220 µCi, the tumors were significantly smaller (0.17 ± 0.21 cm3, P < 0.035) than those mice that received the MTD of 131I-cPAM4.



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  		Fig. 2. Tumor growth curves from individual animals from the untreated and the 700-µCi 131I- and 260-µCi 90Y-cPAM4 treatment groups. The initial tumor sizes were 0.89 ± 13 cm3 (untreated), 0.95 ± 0.15 cm3 (131I), and 0.93 ± 0.17 cm3 (90Y). Tumors were measured weekly as described in "Materials and Methods." Mice were humanely sacrificed when tumor volume exceeded 5.0 cm3. n = number of mice in each group.

 
Survival curves for the untreated, the 700-µCi 131I-cPAM4, and 260-µCi 90Y-DOTA-cPAM4 groups are presented in Fig. 3Citation . The MTD of 90Y-DOTA-cPAM4 provided a significantly longer survival than both the untreated and 700-µCi 131I-cPAM4-treated groups (Table 3)Citation . The relative risk values of the untreated and 131I-cPAM4-treated groups were 17.1 and 15.4, respectively. At the end of the study period (26 weeks), 1 of 10 untreated mice was alive and disease-free. Within the 700-µCi 131I-cPAM4-treated group, two of eight mice were responders (tumor size, <=50% of starting size) for a median of 14 weeks. The remaining six mice had stable disease (tumor size between 50 and 125% of starting size) for a median of 10 weeks. At the end of the study period, one mouse was still alive with no sign of disease by gross and microscopic observation. All seven of the 260-µCi 90Y-DOTA-cPAM4-treated mice were responders, with a median response time of 20 weeks. Six of the seven mice were still alive at week 26 with four mice having no evidence of residual disease. The 220-µCi 90Y-DOTA-cPAM4-treated group was also more affected than the 700-µCi 131I-cPAM4-treated group in terms of survival (P < 0.011); however, the 175-µCi 90Y-DOTA-cPAM4-treated group was not (P < 0.078). There were no significant differences between the survival times for the 175-, 220-, and 260-µCi 90Y-DOTA-cPAM4-treated groups.



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  		Fig. 3. The survival curves generated from the untreated, the 700-µCi 131I-, and the 260-µCi 90Y-cPAM4 treatment groups. The graph represents the percentage of survivors from each group to 26 weeks posttherapy, when the study was ended.

 

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  		Table 3 Statistical analysis comparing the effect of the MTDs of 90Y- and 131I-labeled cPAM4 on survival and tumor growth

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
PAM4 is an IgG1 MAb that recognizes the MUC1 mucin expressed by human pancreatic carcinomas (2) . In preclinical studies, 125I-labeled PAM4 targeted pancreatic tumors with high specificity and could achieve high concentrations of radioisotope within these tumors while minimizing radiation dose delivered to nontumor tissues (3 , 4) . Similar targeting specificity was observed in initial clinical trials (5 , 6) . In experimental RAIT studies, 131I-labeled PAM4 was shown to have significant antitumor effects against both s.c. and orthotopic human pancreatic tumor xenografts (4 , 17) .

Clinical trials of RAIT have met with some success in recent years. Whereas many positive clinical responses have been achieved against lymphomas (18, 19, 20, 21) , solid tumors have had only mixed results (22, 23, 24, 25) . Besides the antibody itself, a major factor influencing the efficacy of RAIT is the choice of radionuclide. Many investigators have reported that the use of residualizing radionuclides, such as 90Y, yields higher concentrations of radioisotope within the tumor, with consequent greater therapeutic effect than can be achieved by use of 131I (9, 10, 11, 12 , 26, 27, 28) . However, others have found that for certain MAbs and tumor types, 131I- could be superior to 90Y-labeled antibodies (29 , 30) .

We examined the biodistribution of cPAM4 labeled with either 111In or 125I in mice bearing s.c. CaPan1 tumors. Similar to what had been reported by others (11 , 26, 27, 28) , we found that, in our tumor model system, there was an ~2-fold increase in %ID/g 111In in the tumor as compared with 125I. However, there was also greater uptake in the liver, spleen, and bone. The uptake in the liver and spleen was not an unexpected outcome, because both these organs are the most active in IgG catabolism (31) and as a residualizing radionuclide, 111In would be retained longer in these tissues than would be the 125I. It should be noted that at the MTD for 90Y-DOTA-cPAM4, the absorbed radiation dose for the liver (1660 cGy) would still be well below the reported toxic level of 3000 cGy in mice (32) . The other tissue of interest, in which free 111In and 90Y can accumulate, is the bone (33) . This is an important consideration, because it adds to the overall radiation dose delivered to the bone marrow, which has been shown to be the dose-limiting tissue of RAIT (22 , 34, 35, 36, 37) . Whereas we did observe a greater %ID/g 111In in the bone, our dosimetry estimates at the MTD of 90Y-DOTA-cPAM4 show that the amount of absorbed radiation dose would be similar to the amount that would be delivered at the MTD of 131I-cPAM4 (429 cGy versus 494 cGy, respectively).

Calculations on theoretical tumor models have suggested that for large tumors (as is the usual clinical presentation of pancreatic cancer), 90Y-labeled MAbs would achieve a higher therapeutic effect in comparison with 131I-labeled MAbs (38) . Supporting this, we found that when administered at their respective MTDs, the 90Y-DOTA-cPAM4-treated mice exhibited a longer period and greater degree of antitumor response than mice that had received 131I-cPAM4. The increased antitumor effects provided by 90Y-DOTA-cPAM4 translated into a significantly longer survival time and cure for approximately one-half of the mice. Similar results were also noted at the lower doses of 90Y-labeled cPAM4 (representing as little as 67% of the MTD).

One of the main antitumor effects of RAIT is at the tumor vascular level (39, 40, 41) . In a previous study, 131I-PAM4 RAIT was found to cause significant suppression of tumor vascular permeability in 1.0-g CaPan1 tumors at radiation doses of 3000 cGy (41) . Even at the lowest doses administered in the current study (130 µCi for 90Y and 350 µCi for 131I), we delivered in excess of 4000 cGy to the tumors. To date, the exact mechanism(s) by which RAIT perturbs the intratumoral vasculature has not been fully elucidated. There is some evidence that the damage caused to the blood vessel is an indirect result via a tumoricidal response rather than direct radiation damage to the vessel itself (40) . It may be that a higher percentage of tumor cells are killed with the 90Y-cPAM4 with a net result of causing a greater degree of damage to existing blood vessels (suppression of vascular permeability) as well as having an antiangiogenic effect. Additional studies need to be done to better understand how 90Y-delivered radiation effect these and other aspects of tumor physiology.

On the basis of the biodistribution data, we estimated that the CaPan1 tumor in both cases would receive approximately the same absorbed radiation dose (~8000 cGy). The clear superiority of 90Y over 131I for PAM4-directed RAIT suggested that factors other then total absorbed tumor dose need to be considered when assessing the efficacy of RAIT. In this respect an important issue affecting the outcome of RAIT may be the heterogeneous distribution of intratumoral radiation dose. The choice of radioisotope may, thus, be critical. For large, bulky tumors, the relatively short pathlength for 131I ß emissions results in a heterogeneous dose distribution attributable to the nonuniform distribution of the antibody within solid tumors. On the other hand, 90Y, having a longer pathlength of radiation emission, can provide for a more uniform dose distribution. That we could obtain similar antitumor effects at lower doses of 90Y-DOTA-cPAM4 further suggests that dose distribution within the tumor may be as important, if not more important, than absolute absorbed dose.

In summary, we found that, at their respective MTDs, 90Y-labeled cPAM4 had a significantly greater antitumor effect than 131I-labeled cPAM4. One of the problems associated with RAIT of solid tumors is the relatively low tumor uptake of administered radiolabeled antibody in the human in comparison with that observed in mice (reviewed in Ref. 42 ). By using 90Y-labeled cPAM4, we were able to demonstrate that this high-energy, residualizing radionuclide, further enhanced the antitumor effect of PAM4-directed RAIT in our tumor-model system, although both isotopes delivered a similar radiation dose to the tumor as a whole. This may allow for a similar enhancement of antitumor effects in patients, even when the relative uptake of antibody remains unchanged. Several approaches are being considered to further increase the antitumor efficacy of 90Y-DOTA-cPAM4. First, the duration and extent of the antitumor response, even at the lower doses, suggests that multiple treatment cycles of 90Y-labeled cPAM4 may provide an effective therapeutic for control of pancreatic cancer. Akin to this approach, others have shown that fractionated doses of RAIT can be more effective than single larger doses (43, 44, 45, 46) . This may be especially appropriate for 90Y, because the bone marrow appears to rebound faster after 90Y administration than after 131I (30) . Finally, we may be able to further increase tumor uptake of 90Y by increasing the total PAM4 protein dose that is administered. We have previously demonstrated that increasing the PAM4 protein dose significantly increases tumor uptake of radiolabeled PAM4, as well as providing a more uniform distribution of the antibody within the tumor (3) . Studies are now underway to determine whether these procedures will further enhance the therapeutic effect of 90Y-DOTA-cPAM4 RAIT for pancreatic cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by NIH Grant CA54425. Back

2 To whom requests for reprints should be addressed, at Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109. Phone: (973) 844-7023; Fax: (973) 844-7020; E-mail: tmc_gscc{at}hotmail.com Back

3 The abbreviations used are: MAb, monoclonal antibody; AUC, area under the curve; cPAM4, chimeric PAM4 antibody; MTD, maximal tolerated dose; RAIT, radioimmunotherapy; DTPA, diethylenetriaminepentaacetic acid; DOTA, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; ITC-Bz-DTPA, isothiocyanatobenzyl DTPA. Back

Received 1/31/01; revised 6/22/01; accepted 6/22/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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