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Biomedical subjects

D P Griswold

Publications and source records attributed to D P Griswold.

At least 19 recordsLinked to original sources
PubMed2000

Minors' rights to refuse medical treatment requested by their parents: remaining issues.

Nurse practitioners are regularly faced with ethical and legal dilemmas when providing care to minors. Laws may not provide clear direction; there may even be conflicting precedents regarding the status of minors, particularly with regard to the juvenile justice system. This article reviews the status of minors' rights with regard to refusing or consenting to medical tests or treatments. Three cases from one author's (DPG) practice illustrate the issues involved.

Adolescent↗
PubMed1992

Cross-resistance of drug-resistant murine P388 leukemias to taxol in vivo.

The antimicrotubule agent taxol (NSC 125973) has shown clinical antitumor activity against several classically refractory tumors. We developed a drug-resistance profile for taxol using ten drug-resistant P388 leukemias to identify potentially useful guides for patient selection for further clinical trials of taxol and possible non-cross-resistant drug combinations with taxol. Multidrug-resistant P388 leukemias exhibited either clear (leukemia resistant to amsacrine) or marginal cross-resistance (leukemias resistant to doxorubicin, actinomycin D, and mitoxantrone) to taxol. Leukemias resistant to vincristine (non-multidrug-resistant leukemia), camptothecin, melphalan, cisplatin, 1-beta-D-arabinofuranosylcytosine, and methotrexate were not cross-resistant to taxol. The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with amsacrine, doxorubicin, actinomycin D, or mitoxantrone and (2) a combination of one of the non-cross-resistant drugs and taxol might exhibit therapeutic synergism.

Animals↗
PubMed1992

Antitumor drug cross-resistance in vivo in a murine P388 leukemia resistant to ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - ylcarbamate 2-hydroxyethanesulfonate hydrate (NSC 370,147) 370147.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- ylcarbamate 2-hydroxyethane-sulfonate hydrate (NSC 370147) is a potent mitotic inhibitor, which has provided the basis for a candidate for clinical trial. As observed with clinically useful drugs, the development of clinical resistance to NSC 370147 will probably be encountered. Information concerning resistance to NSC 370147 should aid in the design of strategies for the optimal clinical use of the drug. A P388 leukemia resistant to NSC 370147 (P388/NSC 370147) was isolated and its in vivo cross-resistance profile was determined. The P388/NSC 370147 line was cross-resistant to vincristine but was not cross-resistant to doxorubicin, etoposide, cisplatin, melphalan, methotrexate, or 5-fluorouracil. This information plus other in vivo cross-resistance data [Waud et al. (1990) Cancer Res 50: 3239] suggests that NSC 370147 may be useful in non-cross-resistant combinations with doxorubicin, melphalan, cisplatin, or methotrexate. The lack of cross-resistance of P388/NSC 370147 to doxorubicin and etoposide shows that resistance to NSC 370147 does not involve multidrug resistance and suggests that the mdr1 gene is not involved in resistance to NSC 370147.

Animals↗
PubMed1992

Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice.

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.

Animals↗
PubMed1991

Practical spontaneous metastasis model for in vivo therapeutic studies using a human melanoma.

In vivo studies aimed at therapy of spontaneous human tumor metastases have been hampered by the lack of practical experimental models. The LOX amelanotic melanoma model described here represents a transplantation model which rapidly and reproducibly results in spontaneous pulmonary metastasis following s.c. inoculation into athymic mice. Pulmonary lesions can be detected using a simple bioassay procedure which is useful for estimation of metastatic cell killing. Using this model we demonstrate that systemic therapy with cyclophosphamide or dacarbazine can produce metastatic cell killing consistent with complete eradication of established pulmonary metastases. This model may also prove useful for future experimental therapeutic studies aimed at prevention of metastases by manipulating tumor staging interval and treatment schedule.

Animals↗
PubMed1991

Preclinical antitumor activity of penclomedine in mice: cross-resistance, schedule dependence, and oral activity against tumor xenografts in brain.

Penclomedine is 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (NSC 338720), an alpha-picoline derivative with p.o. antitumor activity in preclinical leukemia and solid tumor models. Described here are an in vivo cross-resistance profile of penclomedine, treatment schedule dependence studies, and studies exploring the effects of p.o. drug on human tumors xenografted into mouse brain. The latter studies exploited the apparent facile distribution of penclomedine to the central nervous system. Tumor models used included murine leukemia lines selected in vivo for acquired resistance to various antitumor drugs and the human mammary and lung tumor xenografts MX-1 and H82, respectively. The therapeutic effects of p.o. penclomedine against s.c. MX-1 and H82 xenografts were shown to be independent of treatment schedule. Therapeutic activity was comparable when p.o. and parenteral treatments were compared. Lines of P388 leukemia resistant to melphalan, cyclophosphamide, and carmustine were cross-resistant to penclomedine in vivo. Leukemia lines resistant to antimetabolites, DNA binders/intercalators, and vincristine were not cross-resistant to penclomedine. Intracerebrally implanted MX-1 xenografts retained their sensitivity to p.o. penclomedine, and therapeutic activity was at least comparable to that of carmustine, a drug known for its ability to cross the blood-brain barrier. These results demonstrate attributes of penclomedine that are relatively uncommon among currently available antitumor drugs and that are of interest for the anticipated clinical development of this drug.

Administration, Oral↗
PubMed1991

Tumor models in drug development.

In this short essay, we have taken the opportunity to review briefly the history of anticancer drug screening, consider the changes that have been made throughout that history, and reflect on the suitability of current screening practices and the models employed. A major change in emphasis in drug discovery has influenced the development and selection of new model tumor systems as well as screening practices. This new direction, a search for drugs that are selective for particular tumor histotypes, especially solid tumors, was stimulated by the paucity of drugs that have clinical solid tumor activity. The new approach to drug discovery and screening is in itself an experiment. Only time will tell if this approach is successful.

Animals↗
PubMed1991

Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia.

Since 1978, over 50 clinically useful antitumor drugs or new candidate antitumor agents have been evaluated in vivo against cisplatin-resistant P388 leukemia (P388/DDPt) in our laboratories. Analysis of this data base has yielded insights into the cross-resistance, collateral sensitivity, and mechanisms of resistance of P388/DDPt. P388/DDPt was cross-resistant or marginally cross-resistant to eight agents [carmethizole.HCl, rhizoxin, dibromodulcitol, spirohydantoin mustard, hepsulfam, arabinosyl-5-azacytosine (ara-AC), tiazofurin, and deoxyspergualin]. Of these eight agents, the latter six have entered various phases of clinical trials. For these trials, it may be important to exclude or to monitor with extra care patients who have previously been treated with cisplatin. P388/DDPt was collaterally sensitive to six agents [fludarabine phosphate (2-F-ara-AMP), amsacrine (AMSA), mitoxantrone, etoposide (VP-16), batracylin, and flavone acetic acid] and, possibly, to two others (merbarone and echinomycin). These observations of collateral sensitivity suggest that a combination of cisplatin plus any one of these drugs might exhibit therapeutic synergism. Therapeutic synergism has been observed in animal models for combinations of cisplatin plus VP-16, AMSA, or mitoxantrone. The observation of collateral sensitivity for P388/DDPt to four agents (AMSA, mitoxantrone, merbarone, and VP-16) that have been reported to interact with DNA topoisomerase II suggests the possible involvement of the latter in cisplatin resistance. Both the increased sensitivity of P388/DDPt to these agents and a portion of its resistance to cisplatin could be the result of an increase in DNA topoisomerase II activity.

Amsacrine↗
PubMed1990

Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.

Animals↗
PubMed1990

Schedule dependence, activity against natural metastases, and cross-resistance of pyrazine diazohydroxide (sodium salt, NSC 361456) in preclinical models in vivo.

Pyrazine diazohydroxide (sodium salt, NSC 361456; PZDH) is a new antitumor drug with relatively broad activity in initial evaluations against murine leukemias, solid tumors, and two human tumor xenografts in vivo. The present studies were designed to address questions about PZDH activity on different treatment schedules, its activity against metastases, and the extent of its cross-resistance with established drugs. Human LOX amelanotic melanoma xenografts in athymic mice were used to explore schedule dependence and activity against natural metastases, and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. Single-dose treatment and prolonged treatment provided equivalent therapeutic responses to PZDH by both the i.p. and i.v. routes in the i.p. LOX model. A s.c. LOX model resulting in spontaneous pulmonary metastases was adapted for bioassay and quantitation of the numbers of LOX cells killed by PZDH among both primary and metastatic cell populations. It was demonstrated that PZDH afforded about 2-log10 orders of magnitude greater cell kill among pulmonary metastases than against primary s.c. LOX tumors in the same mouse. Murine leukemias resistant to doxorubicin (ADR), vincristine (VCR), cisplatin (DDPt), methotrexate (MTX), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cyclophosphamide (CPA) were not cross-resistant to PZDH. However, both P388 and L1210 leukemia sublines resistant to melphalan (L-PAM) were cross-resistant to PZDH, suggesting that patients previously treated with L-PAM might have less likelihood of response to PZDH than those who had had no opportunity to develop L-PAM resistance. Although these observations should not be applied to clinical studies without due caution, they support clinical evaluation of PZDH as well as continued investigation of its molecular pharmacology.

Animals↗
PubMed1990

Evaluation of combinations of interferons and cytotoxic drugs in murine tumor models in vivo.

This investigation was conducted to provide preclinical in vivo tumor response data collected under standardized conditions with a range of clinically useful drugs combined with type I (alpha/beta) or type II (gamma) interferon. Murine tumor models used were P388 leukemia, Meth A sarcoma, and B16 melanoma. Eleven cytotoxic drugs were studied. Interferon combinations with cytosine arabinoside provided consistent indications of activity greater than that of the respective single agents. Doxorubicin and cisplatin each prolonged the time to treatment failure, relative to single-agent results, when they were combined with gamma-interferon in the Meth A and B16 models. Interferon combinations with methotrexate, 6-mercaptopurine, 6-thioguanine, ampligen, suramin, 5-fluorouracil, cyclophosphamide, and vinblastine yielded no evidence of any positive therapeutic interactions under the conditions of this study.

Animals↗
PubMed1989

Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors.

Penclomedine, a synthetic alpha-picoline derivative, was identified as a potential antitumor agent in the P388 leukemia prescreen of the National Cancer Institute. Upon further evaluation in the National Cancer Institute in vivo tumor panel, the compound demonstrated good activity against two breast tumors. A single i.p. dose or five daily doses caused partial regressions of advanced-stage s.c. implanted mouse CD8F1 mammary adenocarcinomas. Also, penclomedine administered i.p. on Days 1,5, and 9 caused regression of the human MX-1 mammary carcinoma implanted under the renal capsule of athymic mice. In contrast, penclomedine demonstrated only marginal to moderate activity against the i.p. implanted L1210 leukemia and M5076 sarcoma and was inactive in three additional non-breast tumor models (i.p. B16 melanoma, i.v. Lewis lung carcinoma, and s.c. colon adenocarcinoma 38). Penclomedine administered p.o. and i.p. was equally effective against the subrenal capsule MX-1. Doses given p.o. every fourth day caused complete regression of 39 of 40 advanced-stage s.c. implanted MX-1 tumors but were much less effective against human H82 small cell lung carcinomas (13 of 80 complete regressions). Penclomedine p.o. also inhibited growth of the human MCF-7 and mouse 16/C breast adenocarcinomas. Further studies to support the development of penclomedine to clinical trial are in progress.

Animals↗
PubMed1989

Antitumor activity of 2-chloroethyl (methylsulfonyl)methanesulfonate (clomesone, NSC 33847) against selected tumor systems in mice.

Clomesone was evaluated for antitumor activity against a spectrum of animal tumor models. Clomesone exhibited significant antitumor activity against the murine L1210 leukemia implanted i.p., s.c., and intracerebrally (i.c.). Activity against s.c.-implanted tumor was largely independent of schedule and route of administration. Therapeutically optimal single-dose treatment (for tumored mice) was less toxic to nontumored mice than therapeutically optimal prolonged treatment. Clomesone also exhibited activity against other murine tumors (P388 leukemia, B16 melanoma, Lewis lung carcinoma, and M5076 sarcoma). It was active against P388 leukemia sublines resistant to cyclophosphamide, L-phenylalanine mustard, and cis-diamminedichloroplatinum(II). No activity was observed against a P388 subline resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea or against Ridgway osteogenic sarcoma, a nitrosourea-resistant murine solid tumor. Clomesone is generally as effective as the chloroethylnitrosoureas against experimental tumor models. Since clomesone does not have the hydroxyethylating and carbamoylating activities of the chloroethylnitrosoureas (which do not appear to contribute to antitumor activity), it would likely be a more toxicologically selective compound. It may prove to be less carcinogenic than the chloroethylnitrosoureas, and it may contribute less target organ toxicity and less interference with the actions of other drugs when used in combinations.

Animals↗
PubMed1989

Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-beta-D-arabinofuranosylcytosine.

Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.

Alkaloids↗
PubMed1988

Predictive model for plasma concentration-versus-time profiles of investigational anticancer drugs in patients.

We report a model that provides a strong correlation between mouse toxicity data [mouse lethal dose 10% (LD10)] and human plasma concentration-versus-time (CXT) data for 22 commonly used anticancer agents. Mouse toxicity data (LD10) from two dosing schedules, daily times one and daily times seven, were evaluated for the two mouse strains BDF/1 and Swiss. Data from BDF/1 mice were selected for analysis because they were more abundant. Strong correlations were found between LD10 and human plasma CXT data for both daily times one and daily times seven dosing schedules--ln (CXT) = -1.6504 + [0.8408 X ln (LD10)], r = .84, P less than .0001, and ln (CXT) = -0.0754 + [0.8954 X ln (LD10)], r = .90, P less than .0001, respectively. These correlations may serve as useful models to predict the maximally tolerated dose of an investigational anticancer agent prior to entry into clinical trials and to assist in the selection of clinically relevant in vitro CXTs for new-agent screening against human tumors.

Animals↗
PubMed1987

Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy.

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N''-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.

Alkylating Agents↗
PubMed1987

Preclinical antitumor activity and pharmacological properties of deoxyspergualin.

A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.

Administration, Oral↗