Biomedical subjects
Publications and source records attributed to W D Bloomer.
Mouse ovarian tumor (MOT) cells have been grown in C3HeB/FeJ mice as an ascites and as a subcutaneous tumor and in cell culture as a suspension. These cells contain saturable, high-affinity, specific progesterone receptors. Estrogen receptors were not detectable in these cells. MOT cells can be used as both an in vivo and an in vitro model for progestin-mediated radiotherapy.
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An analysis of the human estrogen receptor (ER) mRNA was performed on 71 human breast tumors using an RNase protection assay. Complementary DNA clones to the human estrogen receptor (lambda R8 and lambda R3) were used to generate small antisense 32P-labeled RNA molecules that were hybridized to the tumor RNA. We determined the relative amounts of ER mRNA in each tumor by measuring the amount of RNases A and T1 resistant hybrids. Moreover, because RNase A has the ability to cleave single-base mismatches within RNA/RNA duplexes, we were able to use the assay to screen for possible mutations or deletions in the ER mRNA. A significant correlation was found between the ER mRNA levels and the estrogen binding concentrations determined by a dextran-coated charcoal assay (r = 0.68; P less than 0.0001; n = 58). We also identified a subpopulation of tumors in which a mismatch in the ER mRNA was detected. This message modification, in the B region of the message, significantly correlated with low levels of estrogen binding. This result suggests that the observed B variant might lead to the production of receptors with altered properties.
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Because toxicity with the use of 3,000 centiGray (cGy) of total lymphoid irradiation (TLI) was observed in an earlier study, 2,000-cGy treatments were delivered in a 2-portal format to 7 patients and in a modified 3-portal fashion to 6 patients, as part of a randomized, investigator-blinded trial of TLI treatment for refractory rheumatoid arthritis. Analysis of combined data from the 13 patients revealed statistically significant improvement in 5 clinical indicators of disease activity at the end of TLI and 6 and 12 months later, accompanied by T4-specific immunosuppression. Management considerations resulted in the introduction of prednisone therapy in 5 patients, methotrexate in 4, and azathioprine in 1 during the interval of 8-12 months post-TLI. Herpes zoster occurred in 5 patients prior to the initiation of this additional therapy. These data indicate that, in patients with rheumatoid arthritis, a TLI dose of 2,000 cGy is sufficient to produce measurable benefit that lasts for 6 months, and that the improvement can be maintained at 12 months by the use of prednisone and methotrexate.
Ten patients with advanced squamous cell carcinoma of the uterine cervix received induction chemotherapy with cis-platinum, mitomycin-C, vincristine, and bleomycin (BOMP) over a 5 week period, followed by radiotherapy with concomitant weekly cisplatinum. Two patients were FIGO stage I-B barrel-shaped, five were stage II-B, and three were III-B. All patients responded to induction chemotherapy with five complete and five partial responses. At the completion of radiation therapy, nine patients had negative biopsies. One patient never reached a complete response and died of distant metastasis. Another underwent total exenteration for a central recurrence and was found to have microscopic paraaortic lymph node involvement. A third recurred in the parametrium. Two patients with barrel-shaped tumors underwent extrafascial hysterectomies; both had negative specimens and tolerated surgery well. Although follow-up is short, this new approach for advanced carcinoma of the cervix yielded excellent results and was well tolerated.
A homogeneous dose distribution of radiation to inguinal lymph nodes and deep pelvic structures can be achieved with use of a transmission block over the central portion of a large anterior pelvic-inguinal portal, together with a smaller posterior field. This relatively simple technique permits individualization of isodose distributions and eliminates the problems of matching abutting portals. Reproducibility of daily setup and optimization of machine utilization are both improved.
Substantial interest is currently focused on the alpha-emitting radiohalogen 211At, principally because of its potential use in the radiation therapy of cancer. Knowledge of organoastatine chemistry is incomplete and existing methods for its incorporation restrict the range of compounds which may be labeled. Aryl and vinyl Sn(IV) compounds are notably susceptible to substitution of tin by a variety of electrophiles. We have investigated the reaction of aryltrialkylstannanes with astatine and report here the first examples of astatodestannylation. Formation of aryl astatides proceeds rapidly, cleanly and under mild conditions. The data further elucidate aspects of astatine reactivity and suggest a general route to synthesize astatinated compounds.
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Antibodies that react with antigens on the surface of tumor cells but not normal cells have great potential for cancer detection and therapy. If radiolabeled without loss of immunologic specificity, such antibodies may be able to deliver cytoxic amounts of radiation. Target-cell specificity and a high extraction coefficient are necessary with any radionuclide in order to minimize normal tissue irradiation. Tumor-cell-retention time and the rate of catabolized radionuclide will also influence ultimate applicability. Among the unanswered questions for choosing a radionuclide is the choice of particle emitter. Although classic beta emitters have been used in a number of clinical situations, they have not had a major impact on disease outcome except in diseases of the thyroid. Unfortunately, Auger emitters such as iodine 125 are cytotoxic only when localized within close proximity to the genome. On the other hand, alpha emitters such as astatine 211 eliminate the need for subcellular sequestration but not cell-specific localization.
We have developed an oil- microcentrifuge assay system for analyzing the binding of [3H]estradiol in metabolically active MCF-7 and MDA human breast cancer cells. Complete separation of 2 X 10(6) cells from radioactive media can be achieved within 5 s of centrifugation at 12,000 rpm. The [3H]estradiol binding sites in MCF-7 cells are filled within 20 min of radioligand exposure. Using this assay, our MCF-7 cells contain approximately 15,000 high affinity and saturable binding sites. Binding is inhibited by estradiol and tamoxifen but not progesterone. There is no specific binding of [3H]estradiol in MDA cells. This assay is a rapid, sensitive and reproducible method for investigating hormone-receptor binding and ligand specificity in cultured cells; results compare favorably with those obtained by more complex and lengthy techniques.
We compared the therapeutic efficacy of alpha and beta emitting radiocolloids for the treatment of experimental malignant ascites. 211At is an almost pure alpha-emitter. As 211At-tellurium colloid, the dose survival curve is linear and extrapolates through the origin in a manner similar to other high linear energy transfer radiations. Doses of 25 microCi were curative. Less than curative doses showed a graded prolongation of median survival. In cured mice, long term histological changes were seen in thyroid tissue. Acute changes were seen in the gastrointestinal tract as early as 2 hr after radiocolloid administration; these changes reached a plateau at 6 hr and were essentially gone 36 hr later. By comparison, radiocolloids of the beta emitters 32P, 165Dy and 90Y were not curative, but relatively large doses did substantially prolong median survival. The doses for maximal effect were 150 microCi 32P-chromic phosphate, 8000 microCi ++165Dy-ferric hydroxide macroaggregates and 200 microCi 90Y-citrate. The most compelling reason for the increased therapeutic efficacy of 211At-tellurium colloid is the direct and densely ionizing character of the emitted alpha radiations.
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Auger effects from 125I decay are singularly damaging if localized in DNA as the thymidine analogue 125I-iododeoxyuridine (125IUdR). Recent experience with steroid sex hormones extends these observations by demonstrating cytotoxicity in sites other than the DNA backbone. We have compared the cytotoxicity in human MCF-7 breast cancer cells of 125IUdR, 125I-iodotamoxifen, a nonsteroidal antiestrogen that is translocated from the cytoplasm to the nucleus of receptor containing cells, and 125I-iodoantipyrine, a biological indicator of the body water space. Cytotoxicity is critically dependent upon subcellular localization.
Lymphoscintigraphy is an easily performed noninvasive procedure that offers the potential to detect small numbers of ascitic tumor cells and early diaphragmatic tumor involvement. Moreover, it can be used to delineate and define abnormalities in lymph nodes that are not routinely visualized by bipedal contrast lymphangiography, ultrasound or computed tomography. Lymphoscintigraphy is recommended as an important investigative and adjunctive procedure in diagnosing gynecologic malignancies; there does not appear to be sufficient sensitivity and specificity to justify its routine clinical use.