Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.

BACKGROUND: Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. PATIENTS AND METHODS: In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. RESULTS: Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). CONCLUSIONS: Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. CLINICAL TRIAL: Phase II, comparative two-arm trial (NCT00496288).

Merkel cell carcinoma of unknown primary site.

Merkel cell carcinoma is an uncommon and aggressive primary neuroendocrine skin malignancy which mostly affects the extremities and the head and neck region of elderly patients. Merkel cell carcinoma occurs with increased frequency in sun-exposed areas, in individuals exposed to arsenic and in immunosuppressed patients. Many patients with Merkel cell carcinoma present with other malignancies, mainly skin cancers. Characteristic features are frequent recurrences and regional and distant metastases. Mortality rates range from 20 to 65 per cent. The mainstay of treatment is surgery, with wide local excision, and adjuvant radiotherapy is usually administered. Merkel cell carcinoma of unknown primary site is rare, and the majority of the few cases described have not been from head and neck areas. We present a case of Merkel cell carcinoma of unknown primary site, with upper neck and distant metastases.

Effects of cisplatin on olfactory function in cancer patients.

A prospective analysis of olfaction was performed in 21 patients receiving cisplatin. A reduction in olfactory function was noted in only one patient. Hearing impairment was documented in nine patients, none of whom had impaired sense of smell. We conclude that cisplatin has no major deleterious effect on olfactory function at doses which cause hearing impairment.

Feasibility and low toxicity of early radiotherapy after high-dose chemotherapy and autologous stem cell transplantation for patients with high-risk stage II-III and locally advanced breast carcinoma.

BACKGROUND: This prospective trial examined the feasibility, toxicity, and effectiveness of early locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk American Joint Committee on Cancer (AJCC) Stage II-III and locally advanced breast carcinoma. METHODS: One hundred forty-seven consecutive patients with high-risk and locally advanced breast carcinoma were included in the current study. All patients received induction chemotherapy with a doxorubicin-based therapy, which was consolidated with high-dose cyclophosphamide, carboplatin, and thiotepa followed by autologous stem cell support. Within 50 days of the transplant, the patients were treated with locoregional radiotherapy that included the chest wall or breast, the axilla and supraclavicular area, and the internal mammary chain. The volume of lung included in the treatment volume was kept to a minimum. The central lung distance of the tangential fields ranged from 0.6-2.0 cm (mean, 1.1 cm). Tamoxifen was given based on receptor status. RESULTS: One hundred forty-six of 147 patients received the planned treatment. Only six patients had a delay in the initiation of radiotherapy, and another 16 patients had delays during radiotherapy. Leukocyte and platelet toxicities during radiotherapy were not life-threatening and blood counts thereafter returned to normal. Grade 2 (according to National Cancer Institute Common Toxicity Criteria) skin toxicity occurred in 22% of patients and Grade 3 skin toxicity occurred in 6% of patients. Radiation pneumonitis was reported to occur in 5 patients (< 4%). After a median follow-up of 36 months from diagnosis (range, 6-64 months), there were no long-term organ toxicity and no secondary malignancy reported. No treatment-related deaths were reported. Three patients (< 3%) developed locoregional recurrence. CONCLUSIONS: Locoregional radiotherapy after high-dose chemotherapy and autologous stem cell transplantation appears to be feasible and can be delivered safely within 10 weeks of transplantation. The short-term and long-term toxicity are reported to be low, with good local control.

Pain in the neck after neck dissection.

BACKGROUND: Reports of disability after neck dissection have been directed toward shoulder dysfunction and pain. We could find no report addressing the issue of pain localized to the actual operative site. We have conducted a combined prospective and retrospective study of pain in patients undergoing neck dissection. METHODS: Eighty-eight disease-free patients were evaluated in 3 groups for neck pain. One group was followed up prospectively for 1 to 8 months after surgery, and 2 retrospective groups were followed up for more than 2 years or for 6 months to 2 years. Pain was assessed by a body map and visual analog scale. RESULTS: None of 31 patients followed up for more than 2 years reported neck pain. Four of 27 patients followed up for 6 to 24 months had pain, with a mean visual analog scale score of 3.7. Seventy percent of the prospective group of 30 patients had pain during the first postoperative week, and only 1 patient had pain persisting for more than 2 months. Shoulder pain and disability after radical neck dissection were encountered in all groups, comparable with the incidence reported in the literature. No postoperative neuromas were found. CONCLUSIONS: Chronic pain localized to the operative site is an uncommon occurrence even after radical neck dissection. Chronic pain in the shoulder region may follow radical neck dissection, whereas modified neck dissection is usually a painless procedure.

Incidence of secretory otitis media following maxillectomy.

OBJECTIVE: The purpose of this investigation was to determine the incidence and characteristics of secretory otitis media after maxillectomy procedures. STUDY DESIGN: Retrospective chart analysis was performed with the cases of 49 patients who underwent maxillectomy for tumor in the Departments of Otolaryngology-Head and Neck Surgery and Oral and Maxillofacial Surgery between the years 1990 and 1996. RESULTS: In 10 patients (20%), secretory otitis media manifested itself from 1 week to 6 months after surgery; 1 patient developed a central perforation with chronic otitis media. Nearly one third of patients who underwent total maxillectomy had secretory otitis media. Six patients (8 ears) required insertion of ventilation tubes. CONCLUSIONS: Patients undergoing total and partial maxillectomies are prone to occurrences of secretory otitis media. Insertion of ventilation tubes easily resolves the problem. Preoperative and routine postoperative patient follow-up should always include otoscopy and audiometry, and tympanometry should be performed when warranted.

Pain experienced by patients with terminal head and neck carcinoma.

BACKGROUND: Pain is one of the most feared consequences of cancer and is experienced by up to 80% of patients with head and neck carcinoma (HNC). Pain in terminal HNC patients is common and often defined as severe. This study evaluated the effectiveness of the World Health Organization (WHO) analgesic ladder in the treatment of a cohort of terminal HNC patients. METHODS: The authors prospectively evaluated 62 consecutive terminal HNC patients admitted to the Chaim Sheba Medical Center Tel Hashomer Hospice or the general hospital. Data pertaining to tumor origin, spread, treatment, and results were defined. Pain was assessed with the McGill Pain Questionnaire, using a 10-point visual analogue scale (VAS) and a body map. Pain was diagnosed according to cause and type. Treatment was selected according to the guidelines provided in the WHO analgesic ladder. RESULTS: Only 10 patients suffered from pain that was not locoregional. The results of the VAS score were available in the first reading in all patients with pain (n = 48), with a mean of 4.7 (standard deviation [SD] +/- 2.0). A mean second VAS score obtained 72 hours after the first was 1.9 (SD +/- 1.1). The difference between the two scores was statistically significant (P < 0.001). A third score was available for only 6 patients, with a mean of 1.6. Only 2 patients did not experience improvement of pain after 72 hours of treatment; both of these patients had bony involvement with tumor. Thirty-one patients (65%) were diagnosed with pain of nociceptive origin; these patients were categorized as having actual nociceptive pain (22), nociceptive nerve pain (6), or referred pain to the ear (3). Nonnociceptive pain of neuropathic origin was noted for only 6 patients (12.5%). Pain that could not be well defined but was responsive to opioid analgesic treatment was noted for 11 patients. A different form of non-cancer-related pain was noted for only one patient. CONCLUSIONS: Patients were treated for pain according to the WHO analgesic ladder. They received adequate narcotic analgesics and supportive measures that allowed significant reduction of pain in nearly all cases, with acceptable side effects.

Cellular and secretory mechanisms related to delayed radiation-induced microvessel dysfunction in the spinal cord of rats.

PURPOSE: This study aimed to investigate long-term, radiation-induced changes in microvessel permeability, the profile of the vasoactive mediators endothelin and nitric oxide, and the response of specific cell systems in the irradiated spinal cord of rats. METHODS AND MATERIALS: The thoracolumbar spinal cords of Fischer rats were irradiated to a dose of 15 Gy, and the rats were sacrificed at various times afterward. Endothelin levels and nitric oxide-synthase (NOS) activity were assayed in extracts of spinal cords. Microvascular permeability and the effect of treatment with recombinant human manganese superoxide dismutase (r-hMnSOD) were assessed quantitatively. Immunohistochemistry evaluated astrocytes, microglia, vascular basal membrane, and neurofilaments. RESULTS: None of the rats developed neurologic dysfunction. Endothelin levels were significantly reduced at 18 h after irradiation and markedly attenuated after 10 days (p < 0.007). Thereafter, endothelin levels returned to normal values at 56 days after radiation and escalated to markedly high levels after 120 and 180 days (p < 0.002). NOS activity remained very low throughout the period of follow-up and failed to counterbalance the shifts in endothelin levels. Treatment with r-hMnSOD had no effect on normal vascular permeability but it abolished the abnormally increased permeability measured at 18 h after radiation and again after 120 and 180 days. Standard microscopic evaluation failed to reveal abnormalities in the irradiated spinal cord, but immunohistochemical staining showed a progressive increase in the number of microglial cells per field after 120 and 180 days (p < 0003). A similar increase in the number of astrocytic cells per field was noted after more than 180 days, but an earlier short lasting peak was also noted at 14 days after radiation. No abnormalities were found in blood vessel configuration, density, diameter, and basal membrane staining, or in the neurofilaments. CONCLUSION: Marked imbalance in the regulatory function of endothelium-derived mediators of the vascular tone is present after radiation therapy probably inducing chronic vasoconstriction. This imbalance favors localized procoagulation that may enhance the consequent loss of function measured as increased permeability. Microglial proliferation may account for continuous release of superoxide that may enhance disruption of normal permeability. The latter is corrected by SOD treatment. Astrocytic proliferation may present a response to the mitogenic effect of endothelin and to microglial-derived paracrine effect of cytokines.

Somatostatin-receptor scintigraphy of subcutaneous and thyroid metastases from bronchial carcinoid.

We present a case of bronchial carcinoid tumor with multiple metastases in the retina, subcutaneous tissues and thyroid gland. These metastatic lesions were detected by 111In-pentetreotide scintigraphy 15 yr after removal of the primary tumor. The extensive metastatic involvement documented on scintigraphy spared the patient unnecessary total thyroidectomy and directed the attention of the primary physician to previously unknown and potentially more important foci of metastatic disease.

Sub-additive effect of the combination of radiation and cisplatin in cultured murine and human cell lines.

The use of cisplatin (CDDP) as a potential radiosensitizer in tumors is controversial. Reports about CDDP interaction with radiation range from high radiosensitization to a clear sub-additive effect. We examined the effect of the combination of different concentrations of CDDP with radiation in murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cell lines. CDDP was given in the dose range of 0.01-3.0 micrograms/ml and radiation in the dose range of 1-6 Gy. A methylene blue assay of cell density was used for the evaluation of cell survival and rate of proliferation in 96-microwell plates. The validity of this assay for evaluation of cell survival was verified by colony-forming assay and radiolabeled thymidine uptake. The dose response to CDDP for both OV-1063 and EMT-6 cells lines was examined; the ID50 was 0.06 and 0.9 micrograms/ml respectively. A sub-additive effect of the combination of radiation with CDDP was clearly observed in the two cell lines tested; the increase in dose of each modality resulted in a decrease of the relative contribution on the effect of the other. These findings question the rationale of combining CDDP with radiation for the enhancement of tumor response, since with the increase in the dose of either modality the additional effect of the other decreases.

Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability.

PURPOSE: To investigate the profile of biochemical and physiological changes induced in the rat spinal cord by radiation, over a period of 8 months. METHODS AND MATERIALS: The thoraco-lumbar spinal cords of Fisher rats were irradiated to a dose of 15 Gy. The rats were then followed and killed at various times afterward. Serotonin (5-HT) and its major metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed as well as prostaglandin synthesis. Microvessel permeability was assessed by quantitative evaluation of Evans blue dye extravasation. RESULTS: None of the rats developed neurologic dysfunction, and histologic examination revealed only occasional gliosis in the ventral white matter at 240 days after irradiation. Serotonin levels were unchanged at 2, 14, and 56 days after radiation but increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03). The calculated utilization ratio of serotonin (5-HIAA/5-HT) remained unchanged. Immediately after radiation (at 3 and 24 h) an abrupt but brief increase in the synthesis of prostaglandin-E2 (PGE2), thromboxane (TXB2), and prostacyclin [6 keto-PGF1 alpha (6KPGF)] was noted, which returned to normal at 3 days. This was followed after 7 and 14 days by a significant fall off in synthesis of all three prostaglandins. Thereafter, at 28, 56, 120, and 240 days, escalated production of thromboxane followed, while prostacyclin synthesis remained markedly reduced (-88% of control level at 240 days). Up to 7 days after radiation the calculated TXB2/6KPGF ratio remained balanced, regardless of the observed abrupt early fluctuations in their rate of synthesis. Later, between 7 and 240 days after radiation, a significant imbalance was present which became more pronounced over time. In the first 24 h after radiation, a 104% increase in microvessel permeability was observed which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and 240 days a persistent and significant increase of 98% and 73% respectively above control level was noted. CONCLUSIONS: Radiation induces severe impairment in microvessel function even in the histologically unaffected spinal cord, and alters the secretory phenotype of various cell systems in the central nervous system.

Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy.

Thirty-one (23%) of 137 patients treated for leptomeningeal metastases (LM) achieved a sustained off-therapy response of at least 6 months' duration following treatment by a standard protocol. Of the 31 patients, equal distribution was found among various tumors: lymphoma, 13/44 (29%); breast carcinoma, 10/51 (20%); and other tumors, 8/42 (19%). Neuroimaging of the neuraxis disclosed subarachnoid deposits in 70%, with unexpected findings in 55%. At withdrawal of therapy, all 13 patients with lymphomas had achieved a complete response, and for those with the other tumors, 61% had a partial response. Off-therapy relapse was unrelated to the type of attained response and occurred in nine patients (29%) after a median time of 12 months. Five patients obtained a second prolonged response, mainly by systemic therapy. All eight patients who received only systemic therapy for their LM responded to treatment, four with a complete response. All others received both systemic and intra-CSF treatment and maintained a systemic response. Delayed complications occurred in 58%, with leukoencephalopathy equally affecting patients exposed and patients not exposed to cranial irradiation. The median survival of the whole group was 23 months. We conclude that in LM (lymphomas excluded), a partial response is compatible with a prolonged off-therapy response. Since LM may respond to systemic treatment, the role of intra-CSF therapy, with its associated complications, deserves a prospective reevaluation.

Ethics and the oncologist.

The physician who treats cancer patients is particularly exposed to ethical problems in his daily routine. These ethical dilemmas occur at almost every stage of the cancer patient's treatment from diagnosis through treatment to the final stages of his or her illness. Several of the ethical questions in the treatment of these patients are discussed, particularly the issues of disclosing the diagnosis of cancer to the patient, the place of mutilative surgery and other aggressive modalities in cancer treatment, and the ethics of randomized clinical trials. Awareness of these problems and open discussion will help the oncologist to treat his or her patient in the best possible way.

Schedule dependent tumour growth delay, DNA cross-linking and pharmacokinetic parameters in target tissues with cis-diamminedichloroplatinum(II) and etanidazole with or without hyperthermia or radiation.

It has been reported previously that striking increases in tumour growth delay and cytotoxicity are seen when cis-diamminedichloroplatinum(II) (CDDP) is combined with mild local hyperthermia (43 degrees C, 30 min) and/or etanidazole (ETA). This paper reports a study of CDDP pharmacology and the in vivo tumour DNA cross-linking produced by these combinations. In C3H mice bearing the FSaIIC murine fibrosarcoma, Pt plasma pharmacokinetics were not significantly altered by any of the combination of treatments. Although ETA caused no significant change in CDDP tissue pharmacokinetics, treatment of the tumour-bearing limb with hyperthermia immediately following an i.p. injection of CDDP (10 mg/kg) resulted in an increased peak Pt concentration (3.5 versus 2.8 micrograms Pt/g tumour wet weight) and doubled the t1/2 elimination of Pt (15 to 30 h) from the tumour. Similar heat-induced changes were observed in the Pt pharmacokinetics in skin. There was about a three-fold increase in the Pt area under the curve (AUC) for the tumour, a 1.5-fold increase in the AUC for skin and little change in the AUC for muscle with hyperthermia. When the tumour DNA cross-linking factor (CLF) was determined, it was found that local hyperthermia treatment (43 degrees C, 30 min) increased the CLF of CDDP from 1.7 to 2.7 and hyperthermia (43 degrees C, 1 h) further increased the CLF to 6.1. Misonidazole (MISO) (1 g/kg) increased the CDDP CLF to 2.0, 6.3 and 15.1 in conjunction with 37, 43 (30 min) and 43 degrees C (1 h), respectively. ETA (1 g/kg) was more effective than MISO at increasing the CDDP CLF, producing CLFs of 2.8, 9.1 and 21.5 at 37, 43 (30 min) and 43 degrees C (1 h), respectively. These changes in CLF were reflected in an increased tumour growth delay in the FSaIIC murine fibrosarcoma with CDDP (5 mg/kg) alone from 4.4 to 5.9 days with 43 degrees C (30 min) and then to 11.9 days with ETA (1 g/kg) and 20.9 days with both ETA and local hyperthermia (43 degrees C, 30 min). When CDDP, ETA and hyperthermia were added to a radiation schedule of 300 cGy daily for five days, it was found that giving ETA (1 g/kg), CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) together on day 1 produced the largest tumour growth delay (43 days) and that other schedules which divided the dose of ETA over the other days of the radiation treatment (including one schedule with a second heat treatment on day 4) were significantly inferior.(ABSTRACT TRUNCATED AT 400 WORDS)

The interaction of cisplatin plus etoposide with radiation +/- hyperthermia.

The addition of concurrent etoposide and cisplatin to radiation +/- hyperthermia was evaluated in the murine FSaIIC fibrosarcoma tumor system. Tumor growth delay (TGD) demonstrated that when the drugs were tested with radiation (3 Gy daily X 5) plus (43 degrees X 30 min) local hyperthermia, cisplatin/hyperthermia/radiation (TGD approximately 25 days) was significantly more effective than etoposide/hyperthermia/radiation (TGD approximately 14 days). The addition of etoposide to cisplatin/hyperthermia/radiation, however, yielded a significantly longer growth delay (approximately 34 days). Tumor cell survival studies demonstrated that hyperthermia (43 degrees C, 30 minutes) was dose modifying for etoposide cytotoxicity (dose modifying factor approximately 2.0 as determined by comparisons of the slopes of the curves). The addition of etoposide to cisplatin modified cisplatin killing only slightly at 37 degrees C or 43 degrees C. Considerable additional cell kill was observed over a range of radiation doses with cisplatin, hyperthermia, and etoposide added singly or in combination, especially at the lowest radiation dose tested (5 Gy), but essentially no dose modification was observed. Evaluation of Hoechst 33342 dye-selected tumor subpopulations demonstrated that cisplatin, etoposide, radiation (10 Gy), etoposide plus radiation, and cisplatin plus radiation killed significantly fewer dim (presumably hypoxic) cells than bright (presumably normally oxygenated) cells. Hyperthermia killed more dim than bright cells. The combination of hyperthermia with cisplatin and radiation, however, resulted in approximately 5-fold lesser kill in dim cells, and the addition of etoposide increased this differential to 6.4-fold. These results indicate that etoposide adds small but measurable antitumor effects when used with cisplatin alone or with cisplatin in combination with radiation +/- hyperthermia (especially at lower radiation fraction sizes).

Effect of acidic pH on radiosensitization of FSaIIC cells in vitro by misonidazole, etanidazole, or cis-diamminedichloroplatinum (II).

Because acidic regions may coexist with hypoxic regions in solid tumors, we have studied the effect of acidic extracellular pH on the abilities of misonidazole, etanidazole, and cis-diaminedichloroplatinum(II) (CDDP) to radiosensitize hypoxic FSaIIC cells in vitro. For 1-h exposures to misonidazole prior to and during irradiation, the sensitizer enhancement ratios (SERs) were 2.10 +/- 0.18 at 1 mM drug and 2.50 +/- 0.16 at 5 mM drug at pH 7.40 but only 1.90 +/- 0.14 and 2.30 +/- 0.14, respectively, at pH 6.45. For etanidazole the SERs at pH 7.40 at 1 and 5 mM drug were 1.90 +/- 0.13 and 2.40 +/- 0.18, respectively, but only 1.25 +/- 0.13 and 1.70 +/- 0.17, respectively, at pH 6.45. The decrease in the SERs for both 2-nitroimidazole compounds was statistically significant (P less than 0.01). When CDDP at concentrations of 1 and 5 microM was tested, SERs of 1.30 +/- 0.15 and 1.60 +/- 0.18, respectively, were observed at pH 7.40, and the increase was not significant at pH 6.45 (1.35 +/- 0.15 and 1.80 +/- 0.19, respectively). The cellular levels of misonidazole, etanidazole, and CDDP did not vary significantly at the environmental conditions tested. These results demonstrate that pH is a potentially important variable in the action of hypoxic cell radiosensitizing drugs and suggest that future evaluations of such agents should test the effects of pH.

Interaction with hyperthermia of tetrachloroplatinum(II)(Nile blue)2 and tetrachloroplatinum(II)(neutral red)2 in EMT6 murine cells and the murine FSaIIC fibrosarcoma.

Complexes of the tetrachoroplatinum(II) dianion with positively charged nuclear dyes were prepared in an effort to produce agents which gain ready access into the nucleus and become very cytotoxic at clinically relevant hyperthermia temperatures. Pt(Nile blue)2 and Pt(neutral red)2 are complexes of tetrachloroplatinum(II) with two closely related p-quinonediamine dyes. Pt(Nile blue)2 and Pt(neutral red)2 were only moderately cytotoxic to exponentially growing normally oxygenated or hypoxic EMT6 cells in vitro at pH 7.40 and 37 degrees C. At pH 7.40 and 42 degrees C and especially at 43 degrees C, however, Pt(Nile blue)2 became far more cytotoxic. At pH 6.45 Pt(Nile blue)2 became more toxic toward hypoxic cells (cell kill of 3.5 logs at 500 microM, 42 degrees C for 1 h). Pt(neutral red)2 became much more cytotoxic at pH 6.45 and 42 degrees C or 43 degrees C compared to pH 7.4, and the cell kill observed was similar in both euoxic and hypoxic cells (3 logs at pH 6.45, 43 degrees C with only 100 microM). Tumor cell survival studies in the FSaIIC murine fibrosarcoma demonstrated that both drugs killed in a dose-dependent log-linear manner. Hyperthermia treatment (43 degrees C, 30 min) immediately after either drug resulted in a dose modifying effect. The tumor growth delay produced by Pt(Nile blue)2 (100 mg/kg) was 4.6 days and by Pt(neutral red)2 (100 mg/kg) was 3.8 days. Both drugs were markedly improved by hyperthermia (tumor growth delay 1.4 days for hyperthermia; tumor growth delay 10.9 days for Pt(Nile blue)2 and 8.0 days for Pt(neutral red)2. Intracellular platinum levels were approximately 200 times higher after exposure of EMT6 cells to 25 microM of Pt(Nile blue)2 or Pt(neutral red)2 for 1 h at 37 degrees C than after exposure to the same concentration of cis-diamminedichloroplatinum(II). Treatment of cells with the drugs at 42 degrees C (1 h) resulted in no change in platinum levels with cis-diamminedichloroplatinum(II), but with Pt(Nile blue)2 and Pt(neutral red)2 an increase of 2- to 3-fold was found. Since previous work has shown that both of these complexes are active radiosensitizing agents, these new drugs seem quite well suited for further development as antitumor agents for use against solid tumors alone and in conjunction with hyperthermia and/or radiation therapy.

Interaction with hyperthermia of platinum complexes of triaminotriphenylmethane dyes.

Complexes of the tetrachloroplatinum(II) dianion PtCl4 with positively charged nuclear dyes have been designed in an effort to create new anticancer drugs for use with hyperthermia and/or radiation. The PtCl4 complexes with the monocationic triaminotriphenylmethane dye basic fuchsin [Pt(basic fuchsin)2] and the dicatrionic triaminotriphenylmethane dye methyl green [Pt(methyl green)], as well as the free dyes, were tested in exponentially growing EMT6 cells in vitro. Both the platinum complexes and free dyes were only moderately cytotoxic at pH 7.40 and 37 degrees C in normally oxygenated and hypoxic cells where cell killing by these drugs ranged from 0.5 to 1.5 logs at 500 microM. Each agent, however, became more cytotoxic at hyperthermic temperatures and pH 7.40. Pt(methyl green) and Pt(basic fuchsin)2 were slightly more cytotoxic to euoxic as opposed to hypoxic cells. Both platinum complexes became even more cytotoxic at pH 6.45 and 43 degrees C. Under these conditions, Pt(basic fuchsin)2 killed more hypoxic than euoxic cells (4.5 versus 2.5 logs at 500 microM), but Pt(methyl green) killed more euoxic than hypoxic cells (4.5 versus 2.5 logs at 100 microM). Methyl green was less cytotoxic than Pt(methyl green) at pH 6.45 and 43 degrees C, but basic fuchsin was the most cytotoxic drug under these conditions (cell kill of 3.5 logs in both euoxic and hypoxic cells at 100 microM). Intracellular platinum levels measured after 1 h exposure to 25 microM cisplatin, K2PtCl4, PT(methyl green), and PT(basic fuchsin)2 showed that approximately 1 ng of platinum per 10(6) cells was present after treatment with CDDP at pH 7.40 and pH 6.45 and at 37 degrees C and 42 degrees C; and approximately 0.2 ng was present after exposure to K2PtCl4 under each of these conditions. After exposure to Pt(methyl green), approximately 2.5 ng of platinum per 10(6) cells at pH 7.40, 37 degrees C, and 42 degrees C were present but increased to about 6.5 ng at pH 6.45 and 42 degrees C. With Pt(basic fuchsin)K, 726 ng of platinum were present at 37 degrees C, pH 7.40; 920 ng at 42 degrees C, pH 7.40; 313 ng at 37 degrees C, pH 6.45; and 413 ng at 42 degrees C, pH 6.45. Since Pt(methyl green) was more cytotoxic to cells at pH 6.45 and 42 degrees C, some of this effect could be attributed to increased uptake under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Addition of 2-nitroimidazole radiosensitizers to cis-diamminedichloroplatinum(II) with radiation and with or without hyperthermia in the murine FSaIIC fibrosarcoma.

We have examined the ability of misonidazole (MISO) or etanidazole (ETA) to improve the antitumor efficacy of cisplatin (CDDP), hyperthermia, and radiation in the FSaIIC murine fibrosarcoma. A growth delay of about 25 days was produced with CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) prior to radiation (3 Gy daily for 5 days) on day 1. The addition of MISO (1 g/kg) on day 1 resulted in a tumor growth delay of about 28 days. The addition of ETA at 0.5 g/kg or 1 g/kg resulted in tumor growth delays of about 33 and 43 days, respectively. Tumor cell survival assay showed that MISO was additive with CDDP either at 37 degrees C or with hyperthermia (43 degrees C, 30 min). In contrast, ETA at both 0.5 g/kg and 1 g/kg was dose modifying over the CDDP dosage range at 37 degrees C or 43 degrees C. Analysis of tumor cell killing in Hoechst 33342 selected bright (presumably oxic) and dim (presumably hypoxic) tumor cell subpopulations demonstrated that the addition of MISO to the CDDP trimodality regimen increased killing in the dim cell subpopulation, while the addition of ETA increased tumor cell killing in both subpopulations, although the greater effect was in the dim cell subpopulation. These results indicate that ETA may add to the efficacy of the CDDP trimodality in the clinic and may be of value as a chemosensitizer with CDDP.