Biomedical subjects

T S Herman

Publications and source records attributed to T S Herman.

139 records · Page 8Linked to original sources

PubMedDate not supplied

Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies.

The addition of local hyperthermia to radiation therapy has significantly improved the ability of oncologists to control superficial malignancies. Large tumours, tumours which cannot be heated adequately, and those situated in areas where surrounding normal tissues have decreased radiation tolerance, however, are difficult to eradicate even with this combination treatment. We believe that properly selected and scheduled anticancer drugs will add substantially to the efficacy of local hyperthermia and radiation. A review of the literature concerning the cytotoxic interactions of various anticancer agents with hyperthermia, with radiation and with relevant physiological parameters is presented. From this review, anticancer drugs which are good candidates for trimodality therapy are identified and a general approach to trimodality scheduling is suggested.

Animals↗

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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)

Animals↗

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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)

Animals↗

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Effect of hypoxia and acidosis on the cytotoxicity of six metal(ligand)4(rhodamine-123)2 complexes at normal and hyperthermic temperatures.

Several analogues of PtCl4(Rh-123)2 in which the metal may be Pt or Pd and the coordinated ligand may be -Cl, -CN or -NO2 were prepared and tested in cell culture with EMT-6 cells at normal (37 degrees C) and hyperthermic (42 degrees C and 43 degrees C) temperatures and various environmental conditions (normally oxygenated vs. hypoxic and pH 7.40 vs. pH 6.45). Pd is a much more reactive metal than Pt, while -CN and -NO2 are more tightly bound ligands than is -Cl. The goal of these studies was to define the complex with the least cytotoxicity at 37 degrees C and the greatest enhancement in cytotoxicity under hyperthermic conditions. The Pt complexes Pt(CN)4(Rh-123)2 and Pt(NO2)4(Rh-123)2 were much less cytotoxic than PtCl4(Rh-123)2 under both normothermic and hyperthermic conditions. The Pd complexes were, in general, more cytotoxic than the corresponding Pt complexes. The level of metal (Pt or Pd) in the cells did not appear to be a major factor in the level of cytotoxicity obtained. Complexes which were not cytotoxic at 37 degrees C regardless of oxygenation level or pH did not become cytotoxic at hyperthermic temperatures. In conclusion, the optimal members of this series were the complexes with chloro ligands, indicating that aquation is probably a necessary step in the cytotoxic mechanism and cytotoxicity at 37 degrees C was necessary to obtain cytotoxicity at higher temperatures.

Acidosis↗

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Addition of mitomycin C to cis-diamminedichloroplatinum(II)/hyperthermia/radiation therapy in the FSaIIC fibrosarcoma.

Hyperthermia (temperatures greater than or equal to 42 degrees C) is used clinically to improve the effectiveness of radiation therapy and, although therapeutic gains have been reported, efficacy is limited when tumours are large and/or radiation tolerance is reduced. In order to improve the utility of the hyperthermia/radiation combination we have tested the addition of cisplatin (CDDP) in the laboratory and in the clinic. Our clinical studies have shown that the CDDP/hyperthermia/radiation combination is tolerable and effective, but laboratory investigations demonstrated a relative lack of cytotoxicity in the hypoxic tumour subpopulation. In order to improve the effectiveness of the CDDP/hyperthermia/radiation combination against hypoxic cells we have evaluated the addition of mitomycin C, a hypoxic cell cytotoxic agent to this combination. Mitomycin C (5 mg/kg) i.p. produced a tumour growth delay (TGD) of about 5.3 days in the FSaIIC murine fibrosarcoma; hyperthermia (43 degrees C x 30 min) caused only about 1.4 day TGD and the combination of mitomycin C followed immediately by hyperthermia caused a TGD of about 8.6 days. CDDP (5 mg/kg) i.p. followed by hyperthermia and then 3 Gy on day 1 only of a 5 day x 3 Gy radiation protocol produced a TGD of about 25 days. With the addition of mitomycin C just before CDDP a TGD of about 44 days resulted. Whole tumour excision experiments demonstrated that mitomycin C was highly interactive with CDDP at 37 degrees C and was dose-modifying. When used with CDDP and hyperthermia, however, mitomycin C added little additional cytotoxicity. Hoechst 33342 dye diffusion-determined tumour subpopulation studies indicated a marked effect of the addition of mitomycin C in the dim (enriched in hypoxic cells) subpopulation and nearby equal cytotoxicity in both bright (enriched in euoxic cells) and dim cells resulted. These investigations suggest considerable potential therapeutic efficacy to the addition of mitomycin C to the CDDP/hyperthermia/radiation combination.

Animals↗

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Effect of environmental conditions (pH, oxygenation and temperature) on the cytotoxicity of flavone acetic acid and its dimethylaminoethyl ester.

Bioflavonoids are known to inhibit enzymes in the glycolytic pathway and have been reported to decrease tumour blood flow. The antineoplastic capabilities of flavone acetic acid (FAA), dimethylaminoethyl-flavone-8-acetate (FAA ester) and quercitin (Q) as a function of pH, level of oxygenation and in conjunction with hyperthermia or SR-4233. In vitro, exposure of FSaIIC murine fibrosarcoma cells to various concentrations of FAA or FAA ester for 1 h demonstrated that both drugs were slightly more toxic toward hypoxic cells at 37 degrees C and pH 7.40 (but were somewhat less cytotoxic at pH 6.45 and 37 degrees C) than towards normally oxygenated cells. The cytotoxicity of FAA and FAA ester increased only minimally by concomitant treatment of cells at 42 degrees C or 43 degrees C. When temperatures of tumour-bearing mice anaesthetized with chloral hydrate and pentobarbital were measured both FAA (200 mg/kg) and Q (200 mg/kg) caused a more rapid drop in tumour versus core temperature, indicating a relative shutdown of tumour blood flow had been produced by these flavonoids. In Hoechst 33342 dye-defined subpopulations, both FAA and Q were only minimally cytotoxic in the subpopulation enriched in euoxic (bright) cells, producing surviving fractions of 0.70 and 0.29, respectively but were approximately 2-fold and 3-fold respectively more toxic towards the subpopulation enriched in hypoxic (dim) cells. When FAA preceded hyperthermia approximately a 3-4-fold increase in cell kill resulted from the combination in both subpopulations. Finally, when SR-4233, a selective hypoxic cell cytotoxic agent, was administered prior to FAA or Q and followed by hyperthermia the level of tumour cell killing increased so that the surviving fractions were 0.009 and 0.0055, respectively, in the dim cell subpopulation. These results indicate that FAA, FAA ester and Q may be most effectively used in a setting involving a combined modality regimen with a focus on the hypoxic tumour cell population.

Animals↗

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Whole-body hyperthermia as an adjuvant to treatment with platinum complexes with or without etanidazole in mice bearing the Lewis lung carcinoma or the FSaLL fibrosarcoma.

The response of s.c. primary and metastatic Lewis lung carcinoma to five antitumour platinum complexes with or without tolerable whole-body hyperthermia (60 min to reach temperature then 60 min at 42 degrees C) was examined. The whole-body hyperthermia treatment produced about 2.8 days of tumour growth delay in the s.c. tumours. The addition of whole-body hyperthermia to treatment with each of the platinum complexes was well tolerated by the animals and increases of 1.6-2.0-fold in tumour growth delay resulted with the combined treatment compared with the platinum complexes alone. The combination of etanidazole (1 g/kg) and the platinum complexes followed by whole-body hyperthermia produced marked increases in tumour growth delay ranging from 2.5- to 3.6-fold over the growth delays obtained with the platinum complexes alone. FSaLLC tumour cell survival and bone marrow CFU-GM experiments indicated that local hyperthermia (43 degrees C, 30 min) produced greater potentiation of the cytotoxicity of three platinum complexes than did whole-body hyperthermia (42 degrees C, 60 min). Only the complete treatments including whole-body hyperthermia/etanidazole and the platinum complexes were effective in significantly reducing the numbers of lung metastases formed from s.c. primary tumours. Serum urea nitrogen and creatinine levels were monitored over a time-course post-treatment. Although some treatment combinations caused elevations in these normal tissue parameters by day 12 post-treatment both serum urea nitrogen and serum creatinine returned to the levels of the untreated control animals.

Animals↗

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Summary of studies adding systemic chemotherapy to local hyperthermia and radiation.

The Joint Center-MIT group sought to maximize the efficacy of hyperthermia plus radiation by adding systemic anticancer drugs chosen in the laboratory. After extensive laboratory investigations utilizing primarily the FSaIIC murine fibrosarcoma, we determined that cisplatin was the best drug with which to begin clinical testing and that the sequence cisplatin-->hyperthermia-->radiation was most efficacious. A clinical experience was then gained which found that: (1) the tolerable doses of cisplatin weekly x 6 used with local hyperthermia and radiation (limited by bone marrow suppression) were 50 mg/m2 weekly in chemotherapy naive patients and 30 mg/m2 weekly in patients having had extensive prior drug treatment, (2) apparent complete response occurred in about 50% of patients, and (3) tumour lysis necessitating surgical repair occurred predominantly in patients with recurrent breast cancer in previously heavily irradiated fields where an incidence of 38% was observed as opposed to only 6% in breast cancer patients having had no prior radiation. In an attempt to further improve the local control potential of the combination we tested the addition of other anticancer drugs in the laboratory. Our findings were that both mitomycin C and etanidazole were far better than other agents and were able to double the tumour growth delay produced by the cisplatin/heat/radiation trimodality treatment. Since etanidazole is not marrow suppressive, clinical testing of etanidazole in the trimodality setting along with cisplatin/heat/radiation has been initiated.

Animals↗

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Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours.

Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43 degrees C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration x time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) and a second degree burn in 2/6 fields. None of the five patients experienced peripheral neuropathy, skin ulceration, or needed surgical repair. In addition, there was mild renal toxicity; pharmacokinetic analysis showed a 28-75% increase in the week 1 to week 4 AUC in three patients, all of whom had a decrease in creatinine clearance over the same time of 15-47%. This pilot study suggests this combined modality therapy can be delivered without major complications and that renal function, determined by creatinine clearance, affects clearance of etanidazole and alters the AUC. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic agents such as cisplatin. The impact of etanidazole on the therapeutic index of hyperthermia, radiation therapy and cisplatin may be worth of study, especially since a positive interaction between these modalities is found in laboratory models.

Adult↗

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Response of subpopulations of the FSall C fibrosarcoma to low dose x-rays and various potential enhancing agents.

The effectiveness of various oxygen carrying treatments in sensitizing subpopulations of the FSallC fibrosarcoma to low doses of radiation was assessed, and compared with survivals obtained with the same cells after in vivo irradiation under normally oxygenated or hypoxic conditions. FSallC tumors were treated with 2-10 Gray then the Hoechst 33342 dye diffusion method was used to separate the tumor into bright (enriched in normally oxygenated cells) and dim (enriched in hypoxic cells) subpopulations. There was good agreement between the survival of normally oxygenated cells in culture and bright cells from tumors and between hypoxic cells in culture and dim cells from tumors over a radiation dosage range of 2-5 Gray. At 10 Gray bright cells from tumors were minimally less sensitive to the radiation dose than normally oxygenated cells in vivo. When maximally effective doses of perfluorochemical emulsions (F44E at 4 g PFC/kg or Fluosol-DA at 2.4 g PFC/kg) or a purified bovine hemoglobin solution (PBHS at 1.32 g protein/kg) were administered 1 hr. prior to radiation therapy with carbogen (95% O2, 5% CO2) breathing prior to and during radiation delivery, low single doses of x-ray (2-5 Gray) were measurably more cytotoxic toward both FSallC tumor cell subpopulations. These results indicate that perfluorochemical emulsions or purified bovine hemoglobin preparations along with carbogen breathing may be able to increase tumor radiosensitivity to the relatively low radiation doses per fraction used in the clinic.

Animals↗

PubMedDate not supplied

Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures.

In an effort to synthesize drugs which would become much more cytotoxic at clinically achievable hyperthermic temperatures, complexes of the tetrachloro-platinum(II) dianion were made with two anthracene dye derivatives, MITOX and BISANT, and the acridine dye derivative m-AMSA. As compared with the parent drug, PtCl4(MITOX)2 was less cytotoxic at 37 degrees C and more cytotoxic at 42 degrees C and 43 degrees C especially at pH 6.45. In contrast, the PtCl4(BISANT)2 was more cytotoxic than BISANT under all conditions. M-AMSA was again shown to be less cytotoxic at elevated temperatures but PtCl4(m-AMSA)2 was more cytotoxic especially at 43 degrees C and pH 6.45. Platinum levels in cells treated for 1 hr with 25 microM at 37 degrees C, 42 degrees C and at pH 7.40 versus pH 6.45 demonstrated no significant differences depending on temperature or pH except for PtCl4(MITOX)2 where approximately 4 times higher intracellular platinum levels were present at pH 6.45 versus pH 7.40, although this finding did not correlate with cytotoxicity. These results suggest that PtCl4(MITOX)2 and PtCl4(m-AMSA)2 may be highly interactive drugs with local hyperthermia.

Acidosis↗

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Efficacy of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo.

Pentoxifylline, a methylxanthine that is used to treat veno-occlusive disease, can increase perfusion in undervascularized tissues. Addition of high concentrations, like caffeine, causes progression through radiation or drug induced G2 phase blocks, thereby limiting time for repair of DNA breaks and crosslinks. We have examined the potential of pentoxifylline to augment the effects of antitumor alkylating agents in vitro and in vivo. In MCF-7 human breast cancer cells in vitro, pentoxifylline (2 mM) present for 24 h was only slightly cytotoxic (approximately 10% cell kill at 2 mM), but when present prior to and during AA it increased the cytotoxicity of CDDP by 2 logs at 250 microM. With L-PAM in vitro, pentoxifylline was much less effective and only at a concentration of 250 microM L-PAM did 2 mM pentoxifylline increase cytotoxicity (approximately 0.3 logs). In the FSaIIC murine fibrosarcoma system, 100 mg/kg of pentoxifylline i.p. immediately prior to the alkylating agent or 50 mg/kg x 5 of pentoxifylline over 24 h with the alkylating agent given immediately after the third dose increased the tumor cell kill achieved by CDDP, carboplatin, cyclophosphamide, and thiotepa. The increase in tumor cell killing was modest (2.9-fold). Pentoxifylline in the multiple dose regimen (50 mg/kg x 5 over 24 h) was more effective than in the single dose (100 mg/kg) protocol. In the EMT6 mouse mammary adenocarcinoma, pentoxifylline (100 mg/kg daily x 5) improved the tumor growth delay produced by CDDP (3.3 mg/kg alternate days x 3), carboplatin (25 mg/kg daily x 5), cyclophosphamide (100 mg/kg alternate days x 3) and thiotepa 5 mg/kg (daily x 5). Only with cyclophosphamide, however, did the interaction appear to be large, as a 2.4-fold increase was observed.

Alkylating Agents↗

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A carbonic anhydrase inhibitor as a potential modulator of cancer therapies.

Since several anticancer drugs are known to become more cytotoxic to cells in an acidic milieu, we have attempted to utilize the carbonic anhydrase inhibitor, Acetazolamide, to acidify the blood and tumor of C3H mice bearing the FSaIIC fibrosarcoma in order to sensitize tumor cells in vivo to CDDP, Melphalan, BCNU, SR4233 or PtCl4 (Fast Black)2 +/- hyperthermia. The direct cytotoxic interactions between the anticancer drugs and Acetazolamide were tested in FSaIIC cells in vitro with the monacidifying diuretic Chlorothrozide as a control. When cells were exposed to CDDP both diuretics protected against cytotoxicity in a dose dependent fashion. In contrast, cells exposed to Melphalan were minimally sensitized and those exposed to BCNU, SR4233, or PtCl4 (Fast Black)2 were essentially unaffected by the presence of the diuretic agents. Both diuretics were essentially non-toxic to cells in vitro, and, interestingly, both drugs markedly protected cells against hyperthermia under low pH conditions. In vitro, however, Acetzolamide produced a tumor growth delay of 2.3 days alone when given at 10 mg/kg i.p. once (the most effective dose) and produced additive growth delays with CDDP and Melphalan, but probably greater than additive delays with SR4233 and PtCl4 (Fast Black)2. When Acetazolamide was given daily for 5 days starting on the day the anticancer drugs were given once (day 7) essentially no further increase in tumor growth delay of nearly 16 days was observed versus only 4,6 days for the drug alone. When hyperthermia (43 degrees C min.) was delivered locally to the tumor after i.p. injection of the drugs, further growth delays were produced for every drug combination which probably were additive in extent. Blood and urine pH determinations revealed that a pH drop of 1 units occurred in the blood and a pH elevation of 1 to 21 units occurred in the urine 1 hr. after i.p. injection of Acetazolamide. These results indicate that this carbonic anhydrase inhibitor can add to the anticancer activity of the drugs tested. The mechanism may involve its ability to acidify the intratumoral environment, but other mechanisms can not be excluded.

Acetazolamide↗