Schedule Dependency of Orally Administered

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Aug 1, 1994 - Mark J. McKeage, Lloyd R. Kelland, Frances E. Boxall, et al. in Vivo ..... in oral absorption since there were no changes in total plasma plati.
Schedule Dependency of Orally Administered Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in Vivo Mark J. McKeage, Lloyd R. Kelland, Frances E. Boxall, et al. Cancer Res 1994;54:4118-4122. Published online August 1, 1994.

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[CANCER RESEARCH54, 4118-4122, August 1, 19941

Schedule Dependency of Orally Administered Bis-acetato-ammine-dichioro cyclohexylamine-platinum(IV) (JM216) in Vivot Mark J. McKeage,2'@ Lloyd R. Kelland, Frances K Boxall, Melanie it Valenti, Mervyn Jones, Phyllis M. Goddard, Jean Gwynne, and Kenneth R. Harrap Drug Development Section@ The Institute ofCancer

Researck

Block E, 15 Cotswold Roa4 Belmonz Suuon@Surrey SM2 5NG, United Kingdom

ABSTRACT JM216 is a novel antitumor platlnum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neu rotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma)

and

a human

tumor

model

(PXN1O9T/C

ovarian

carci

noma xenograft) was studied in vivo. Single dose (q2ld), once a day dosing for 5 consecutive days (q2ld or q2Sd), and once a day dosing indefinitely (chronic

daily dosing) administration

schedules

were compared.

Against

the murine ADJ/PC6 plasmacytoma, daily xS administration improved the tolerance, antitumor potency, and therapeutic index of oral JM216, compared

to single dose administration,

whereas no advantage

was found

for fractionating cisplatin dosages. Against the PXN1O9T/Chuman ovar ian carcinoma xenograft, oral JM216, given at dose levels delivering a equivalent mg/kg/day

total dose on single dose (200 mg/kg q2ld), daily x5 (40 q2ld) and chronic daily dosing (9.5 mgfkaJd) schedules,

showed superior tumor growth delays (55 ±15 days; P < 0.05) and maximal tumor regression (10 ± 11% of initial tumor volume; P < 0.001) with the daily xS schedule. Gastrointestinal toxicity (P < 0.05) and mild nephrotoxicity (P < 0.01) complicated the chronic daily dosing schedule, while leukopenia (P < 0.02) and thrombocyto penia (P < 0.01) were dose-limiting for the single dose and daily xS administration, respectively. Peak plasma ultrafiltrate (PUF) platinum levels were below cytotoxic levels (PUF Cmax, 0.11 ±0.066 mg/I) at the maximally tolerable dose for the chronic dosing schedule (9.5 mg/kgJ. Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 ±0.11 mg/I) to 200 mg/kg (PUF Cmax, 2.4 ±0.44 mg/I; P > 0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after Its oral administration to mice. Optimal anti

tumor activity, tolerance, and pharmacoidnetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration

schedule.

INTRODUCTION

resistance,

and,

unlike

cisplatin,

displays

marked

Received 11/3/93; accepted 6/1/94. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. work

was

supported

by grants

to the

Institute

of Cancer

Research

by the Cancer

Research Campaign (United Kingdom), the Medical Research Council, The Johnson Matthey Technology Centre, and Bristol Myers Squibb Oncology. 2 To

whom

3 Present

requests address:

for

reprints

Oncology

should

Research

be

addressed.

Centre,

Institute

of

Oncology,

The

Prince

of

Wales Hospital, High Street, Randwick, Sydney NSW 2031, Australia. 4 The abbreviations used are: JM216,

days results in improved

tumor

response rates (from 10 to 89%) with changes in neither the incidence nor severity of toxicity (8). Continuous protracted i.v. infusions of the antimetabolite 5-fluorouracil results in improved response rates in advanced colorectal carcinoma and also reduced hematological and gastrointestinal toxicity, in comparison antitumor action of the existing clinical

to bolus schedules (9). The platinum drags do not appear

dependent upon administration schedule (10), while their toxic effects are schedule

dependent

since the myelosuppression

and neurotoxicity

of cisplatin is more prominent with daily X5 administration (11, 12), whereas its nephrotoxicity and emesis are worse with single dose administration (12—is). This paper describes antitumor schedule dependence for oral JM216 against a murine and a human tumor model in vivo. A cisplatin..responsive human ovarian carcinoma xenograft, PXN1O9T/ C (16), was used which would be expected to be sensitive to changes in dosage and schedule of administration. Single dose administration was compared to two divided dose schedules in which oral JM2i6 was given either once a day for 5 consecutive days or once a day continuously. The schedule dependency of antitumor activity was related to plasma pharmacokinetics at equivalent total dose levels for the three administration schedules. The effect of schedule on hema tological toxicity and renal function at equitoxic doses was also investigated. Additionally, the comparative antitumor effects of i.p. given as either a single dose or once daily for

5 consecutive days against the solid murine AD/PC6 plasmacytoma was investigated.

time

dependency of its in vitro cytotoxic action (1). JM216 has oral antitumor activity and bioavailabiity in mice bearing murine and human tumors (1, 2). Rodent toxiciological studies have shown dose

1 ibis

once a day doses for 5 consecutive

cisplatin and oral JM2i6

JM2164 is a lipophilic platinum(IV) complex with in vitro activity against human tumor cell lines both sensitive and resistant to cisplatin (1). It shows a partial lack of cross-resistance to cisplatin in models of acquired

limiting rnyelosuppression, a lack of nephro- and neurotoxicity, and less gastrointestinal toxicity than i.v. cisplatin and i.v. carboplatin (3—5).JM216 has been selected for clinical testing as an orally administered platinum drug (6, 7). The optimal administration sched ule has not yet been identified. The marked time-dependence of its in vitro activity prompted this in vivo comparison of single dose and fractionated administration schedules. Schedule is an important factor influencing the efficacy and toler ance of cancer chemotherapy. In small cell lung cancer, fractionation of the single daily dose of the topoisomerase inhibitor etoposide into

bis-acetato-ammine-dichloro-cyclohexylamine

platinum(IV); M'fD, maximally tolerable dose; ED,.,, 90% of the effective dose; LD@, 50% of lethal dose; AUC, area under the concentration-time curve; cisplatin, cis-diam

minedichloroplatinum(II); Cmax, peak plasma concentration; Pt, platinum; PUF, plasma ultrafiltrate.

MATERIALS AND METhODS Drug Administration.

JM216 was synthesized and supplied by the John

son Matthey Technology Centre, Blount's Court, Sonning Common, Reading, Berkshire RG4 9NH, United Kingdom. 1M216 was suspended in arachis oil (10 mgfkg) by sonication (MSE 150 Watt Ultrasonic Disintegrator, 15 @m for 15 s) immediately

before being given by oral gavage.

JM216

was administered

either as a single dose repeated once every 21 days (single dose q2ld), once a day for 5 consecutive days repeated once every 21 or 28 days (daily X5 q2ld or daily X5 q28d), or once a day indefinitely (chronic daily dosing). Cisplatin was dissolved in sterile sodium chloride (0.9% w/v) by sonication (MSE 150 watt Ultrasonic Disintegrator,

15 ,.@mfor 15 s) and given i.p. as a single dose

or once a day for 5 consecutive days. Assessment of Antitumor Activity. A human ovarian carcinoma xc nograft (PXN1O9T/C),whose biological properties have been described pre viously, was used for this work (16). This xenograft has been established from a cell line, which in turn was raised from an ascites sample taken from a patient

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SCHEDULE DEPENDENCY OF ORAL JM216

with poorly differentiated papillary adenocarcinoma of the ovary. The patient had a history of clinical responses to cisplatin and carboplatin prior to the collection of the sample. The xenografted tumor has been shown previously to be of human karyotype, histologically similar to the original explant, and sensitive to cisplatin, carboplatin, and iproplatin. Its doubling time has been estimated to be 8.4 days (16). under halothane anaesthesia using a 2-mm2fragment. Animals were housed in negative pressure flexible film isolators and maintained on Labsure 21% protein diet (irradiated at 2.5 Mrads) with access to autoclaved tapwater ad libitum. Mice bearing comparably sized tumors were randomized into treat ment or control groups (6—10mice). JM216 was given orally on single dose

q2ld, daily X5 q2ld, daily X5 q28 day, and chronic daily dosing adminis Control animals were

treated with the oral drug vehicle according to the respective schedule. Tumor diameters, (a) and (b), were measured with a slide calliper, where (a) is the

longest diameter and (b) is the longest diameter at right angles to (a). Tumor volumes (@Owere calculated according to the equation V a X b2 X ir/6 and were normalized to the volume at the start of treatment. The ratio of mean tumor

volume

of treated

and control

groups

(T:C) was defined

clearance

as previously

described

(18) 96 h after the last dose of oral JM216

given as a single dose, once a day for 5 consecutive days, or once a day

Implants were made s.c. to female nude (nu/nu) mice (aged 6 to 8 weeks)

tration schedules at doses up to an approximate MiD.

the treatment course (16% body weight loss, day 17), necessitating cessation of treatment. Blood was collected for the determination of peripheral blood counts from an axillary incision during terminal halothane anesthesia into tubes containing EDTA (1 mg) from three mice each at 0, 2, 4, 7, 10, 14, 17, 21, 31, and 35 days. The glomerular filtration rate was determined by inulin

as the ratio of

continuously for 21 days at the MTD with six mice at each data point. Pharmacokinetics. Pharmacokinetic studies were undertaken in female BALB/c mice aged 8 to 10 weeks after single oral doses of JM216 at 9.5

mg/kg, 40 mg/kg, and 200 mg/kg and on the fifth day of a daily X5 treatment course at 40 mg/kg/day X5. Blood was collected under terminal halothane anaesthesia from three mice after oral JM216 at 0, 10, 20, 30, and 60 mm and 2, 3, 4, 6, and 8 h after drug ingestion into tubes containing heparin (10 units) for plasma total platinum and plasma ultrafiltrate platinum analysis. Blood samples were centrifuged (2000 X g for 5 mm at 4°C)immediately after collection to prepare plasma. A aliquot was set aside on ice for plasma total

platinum analysis. An ultrafiltrate sample was prepared immediately from the remaining plasma using an Amicon Centrifree Filter (M130,000 cutoff; Ami con, Beverly, MA). The filters were centrifuged at 2000 X g for 20 mm at 4°C.

the mean relative tumor volume in treated and control groups and was calcu lated at 28 days, since this was an acceptable duration for survival for untreated

Platinum analysis was undertaken by flameless atomic absorption spectrome try using a Perkin Elmer Spectrometer (Models 1100B and HGA700; Perkin

control animals bearing this xenografted tumor. Maximum tumor regression was defined as the smallest relative tumor volume achieved throughout a

Elmer, Ueberlingen, Federal Republic of Germany). Absorption was measured at 265.9 nm. Platinum concentrations were calculated by an external standard

treatment course. The growth delay was the difference in time required for the tumor to double in volume. The growth and assessment of antitumor activity of the solid ADJIPC6 plasmacytoma was as previously described (1, 17). Briefly, 20 days after s.c

curve.

implantation

of platinum concentration versus time was taken as the absorption rate constant (K,). The mean residence time was estimated by dividing the AUC by the

of i-mm@ tumor

fragments,

animals

bearing

comparably

sized

tumors were randomized (3 per dose level and 10 vehicle controls). Cisplatin and JM216 were administered as a single dose or daily for 5 consecutive days. Ten days later, tumors were dissected out, and the weights of control and treated groups were compared. Antitumor activity was defined in terms of a “therapeuticindex,―the ratio of the 50% lethal dose to ED@.

Toxicology Studies. Female BALB/c mice aged 8 to 10 weeks were used. The MTD was defined as a dose causing significant and reversible body weight loss (5 to 20%) but no moribundity that was 25% below a dose causing moribundity. The MTD for oral JM216 given on a single dose administration schedule was as defined previously (200 mg/kg; Ref. 3). The MTD for oral JM216 given once a day for 5 consecutive days was 55 mg/kg/day, since this caused reversible body weight loss (13.4%) but no moribundity, while mon bundity

was observed

at higher

dose

levels

of this schedule

(frequency

of

moribundity: 60 mg/kg day X5, 1 of6; 70 mg/kg day X5, 4 of 6; 80 mg/kg day

x5, 6 of 6). The MTD for oral JM216 given once a day continuously was 15 mg/kg/day, since a higher dose level (20 mg/mg/day) was associated with progressive loss of body weight and deterioration in general condition early in

The

area

under

the

platinum

concentration

versus

time

increasing and by the logarithmic trapezoid rule when successive values were decreasing, up to 8 h. The slope of the input phase on a semilogarithmic plot

AUMC and corrected for the mean absorption time by subtracting the inverse

of the absorption rate constant. The free plasma platinum fraction was assessed by dividing the free plasma platinum AUC by the total plasma platinum AUC and expressing

the fraction

Statistics.

The significance

as a percentage. of differences

between

means

were

assessed

using a t test. P < 0.05 was regarded as significant.

RESULTS The antitumor activity of oral JM216 and i.v. cisplatin given as either a single dose or once daily for five consecutive days was compared in the murine ADJIPC6 plasmacytoma model. Neither the toxicity, antitumor potency, nor the therapeutic index changed when i.v. cisplatin was given as a fractionated rather than a single dose (cisplatin single dose: LD50, 11.5 mg/kg; ED@, 0.88 mg/kg; TI 13;

Table 1ovarianScheduleDose Antitumor activityof oral JM216 given eitheras a singledose, once a day for 5 cousecutive days, or once a do indefinitelyto nude mice bearinghuman carcinoma xenografts (PXNJO9T/C)y

T:C ratio― dose q21 days100 0/6Daily

regression

Day 28

F' P > 0.02) or daily X5 dosing (6.2 ± 3.7% loss of body weight compared to controls; 0.02 > P > 0.01). In BALB/c mice, hemato logical toxicity occurred with all administration schedules at the The severity

regimens,

0

Total

AUCn@ h

(mg/hr/l @‘) (h)

of leukopenia

was greater

with single dose JM216

[nadir, peripheral WBC count: 1.2 ±0.4 (lO9Iliter); day 2] than with daily X5 dosing [nadir, peripheral WBC count: 2.7 ±0.1 (10@Il);day 12; P < 0.02]. Conversely, the severity of thrombocytopenia was worse with the daily X5 regimen [nadir, platelet count: 159 ±39 (109/liters); day 14] than with single dose administration (nadir, platelet count: 541 ±92; day 10; P < 0.01). No significant reduction in [‘4C]inulinclearance was recorded with the single dose or daily X5

@‘600

I:

1

3200 5

MTh. 800

40, or 260

were also studied on day 5 ofa 40 mg/kg/day X5 treatment

? 40 da@

80

l@ days

but a small

reduction

occurred

with chronic

daily dosing

(—11% of control; P < 0.01). Plasma total and ultrafiltrate platinum pharmacokinetics were stud led in mice after JM216 orally at 9.5, 40, and 200 mg/kg (Table 2; Fig. 2), doses corresponding to the delivery of a equivalent total dose of 200 mg/kg per 21 days for the three administration schedules. Peak ultrafiltrate platinum levels increased by over 10-fold with only a 4-fold increase in dose from 9.5 mg/kg (PUP Cmax, 0.11 ±0.066 mg/i) to 40 mg/kg (PUF Cmax, 1.5 ±0.11 mg/I; P < 0.01) but then did not significantly increase (1.6-fold) with a further 5-fold increase in dose from 40 to 200 mg/kg (PUF Cmax, 2.4 ±0.44 mg/I; P > 0.05). Similarly, peak total platinum levels increased by over 8-fold with only a 4-fold increase in dose from 9.5 mg/kg (Total Cmax, 0.37 ±0.15 mgfl) to 40 mg/kg (Total Cmax, 3.0 ± 0.31 mg/l; P < 0.001) but then did not significantly increase (2.4-fold) with a further

5-fold

increase

in dose from 40 to 200 mg/kg

(Total

Cmax,

5.7 ±0.44 mg/l; P > 0.05). Total and ultrafilterable plasma platinum AUCS also increased disproportionately by about 10-fold with only a 4-fold increase in dosage from 9.5 mg/kg (AUC0_8 h: total 1.3 mghF1; PUF 0.18 mg.h.l1) to 40 mg/kg (AUCO.8 1,: total 14 mg@hl@; PUF 1.7 mg.h.l@) but then increased less than proportion ately (2-fold) with a further 5-fold increase in dose from 40 to 200 days days mg/kg (AUCIJ_8 h: total 25 mgh1'; PUF 3.5 mghl'). Tmax, Fig. 1. Tumor growth curves of a human ovarian carcinoma xenografted tumor MRT, and Ka showed no dose related changes. A comparison of (PXN1O9T/C) in nude mice treated with oral JM216 as a single dose (q2ld) [A: 0, pharmacokinetics on days 1 and 5 of a 40 mg/kg/day X5 regimen control; @,100 mg/kg; •,200 mg/kg; arrows@ time of treatment], once a day dosing for showed no change in total plasma platinum Cmax (day 1, 3.0 ±0.31 5 consecutive days (q2ld) [B: 0, control; 0, 20 mg/kg/day; t@,40 mg/kg/day; •,60 mg/k&Jday;solid bars, time of treatment], once a day dosing for 5 consecutive days (q28d) mg/l; day 5, 2.9 ±0.60 mg/I; P > 0.05) or AUC (day 1, 14 mghF1; [C: 0, control; 0, 20 mg/kg/thy; @, 40 mg/kg/day; •,60 mg/kg/day; solid bars, time of day 5, 14 mgh1@). However, decreases in ultrafilterable plasma treatmenti, or once a day doses indefinitely (chronic daily dosing), [D: 0, control; 0, 9.5 mg/kg/day; @,14.3 mg/kg/day; •,20 mg/kg/day; solid bar, period of treatment]. platinum Cmax (day 1, 1.5 ±0.11 mgfl; day 5, 0.59 ±0.099 mgfl; 4120

a

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Downloaded from cancerres.aacrjournals.org on July 14, 2011 Copyright © 1994 American Association for Cancer Research

SCHEDULE DEPENDENCY OF ORAL JM216

peak plasma ultrafiltrate levels were 0.62 ,.LM,whereas the IC50 (2-h)

Total plasma

for JM216 0

@

a

20

4'

C •UC)

0.

10

x 0 a

in the cell line from which

chronic dosing schedule

xenograft

is due to plasma drug levels failing to reach

cytotoxic concentrations for an adequate time. Nonlinear pharmacokinetic behavior is characterized by dispropor

C)

tionate changes 00

50

100 150 dose (mg/kg)

Plasma

200

Following

in drag levels and AUC with changes

oral JM216

at 9.5 and 40 mg/kg,

t@traf1ltrate

4,

increase

0.

Cmax

in dose from 40 mg/kg

to 200 mg/kg

(the MTD

for single

dose administration) was accompanied by less than proportionate (about 2-fold) increases in plasma platinum Cmax and AUC, consist

@1.7 I,

ent with a dose-related

a

0

100

in dosage (20).

plasma platinum

and AUCS in mice increased by 10-fold and out of proportion to this 4-fold increase in dosage. This effect may be due to a dose-related increase in the extent of oral absorption. Platinum drugs effect gas trointestinal mobility and transient time6 and such phenomena could be a basis for an apparent dose-related enhancement of oral absorp tion, such as seen in this dose range. .Conversely, a further 5-fold

0

150

dose (mg/kg) Fig. 2. Dose-relationship ofCmax(•)and AUCQ_8 h(O)for total plasma platinum (A)

and ultrafiltrateplasmaplatinum(B) in mice treatedwith oralJM216 [predictedincrease in (i) Cmax (dashed line) and (ii) AUC (dotted line)].

fall in the extent of drag absorption.

A Phase

I study of oral JM216 made a similar finding of an apparent reduction in the extent of drug absorption and less than proportionate increases in Cmax and AUC with dose escalation above 200 mg/rn2 (6). We hypothesize that this finding may relate to the poor aqueous solubility of JM216, trointestinal

limiting

dissolution

from its dosage

tract and availability

for absorption

form within the gas as dosages

exceed

its

P < 0.001), AUC (day 1, 1.7 mghl'; day 5, 0.97 mghr') and free plasma fraction (PUF AUC0.8 @,fFotalAUC0...8 h: day 1; 12% : day 5; 6.9%) were recorded on day 5 compared to day 1.

limit of solubility. Interestingly, a similar pattern of nonlinear phar macokinetic behavior has been reported for etoposide, an oral anti cancer agent with schedule-dependent properties and poor aqueous solubility (21). The complex nonlinear pharmacokinetic behavior of oral JM216 in mice meant that optimal plasma pharmacokinetics occurred at dosages used in the daily X5 administration schedules and

DISCUSSION

may be the basis for the in vivo antitumor schedule

We have demonstrated the dependence upon administration sched ule of the antitumor activity of a novel oral platinum agent (JM216) independently in two in vivo tumor models. Against the murine ADJ/PC6 plasmacytoma, daily X5 administration of oral JM216 resulted in improved tolerance, antitumor potency, and therapeutic index compared to single dose administration. Against a human ovar ian carcinoma

xenograft,

antitumor

activity

was best for daily

be daily X5 dosing, since this schedule showed the best activity and tolerance in these preclinical model systems. Further experiments addressed the pharmacokinetics of oral JM216 and the possible mechanistic basis of its in vivo antitumor schedule dependency. At the MTD for the chronic dosing schedule (9.5 mg/kg),

dependancy

of the

drug in these model systems. A further pharmacokinetic comparison in mice treated with oral JM216 found falls in ultrafilterable plasma platinum Cmax, AUC, and free fraction on the fifth compared to the first day of a daily X5 ad ministration

schedule.

This finding did not appear due to a reduction

in oral absorption since there were no changes in total plasma plati num Cmax

X5

administration compared to single dose or once daily dosing indefi nitely administration schedules, both at their respective MTDs and at dose levels delivering an equivalent amount of total drug. In contrast, antitumor schedule dependency is not a well recognized property of either the existing clinical platinum drugs (10) or alkylating agents (19). In keeping with this, we found no advantage for a fractionated schedule (daily X5) of cisplatin compared to its single dose admin istration in the murine ADJIPC6 plasmacytoma. Small functional differences in toxicity were found with the different schedules of oral JM216, such as mild nephrotoxicity and greater body weight loss, suggestive of more severe gastrointestinal toxicity with chronic daily dosing and more severe thrombocytopema and less leukopenia with daily X5 dosing. These data show that oral JM216 has antitumor schedule dependent properties in vivo, which is an unusual feature for this class of agent, and suggest that the optimal clinical protocol may

@

the PXN1O9T/C

tumor was established is 2.7 P.M.5 Previous work has demonstrated that the cytotoxicity of JM216 is highly time dependent, with optimal in vitro activity occurring with drug exposure durations of 24 to 96 h (1). This suggests that the poor in vivo antitumor activity of the

or AUC

over

a 5-day

treatment

period.

JM216

is a

platinum(IV) complex, and such complexes are thought to require activation by reduction to platinum(II) species as a prelude to inter actions with biological macromolecules (22). In keeping with this, metabolism studies have found very little parent JM216 after its oral administration in rodent or human plasma but a series of platinum(II) metabolites

including

ammine-dichloro-cyclohexylamine-platinum

(II) (JM1 18) (23). This suggests that JM216 is a pro-drug and that the time-dependent changes in plasma ultrafiltrable platinum pharmaco kinetics may relate to the induction of its activation to platinum(II) metabolites.

In summary, oral JM216 displays antiturnor schedule dependency in vivo in preclinical tumor model systems and nonlinear pharmaco kinetics after its oral administration to mice. Its schedule-dependent properties

appear to relate to dose-related

changes

in the extent of

absorption. Optimal antitumor activity, tolerance, and pharmacokinet ics occurred with daily X5 dosing, and these findings have prompted the clinical

evaluation

of a daily X5 administration

5 L

R. Kelland,

unpublished

6

E. Morgan,

personal

data.

communication.

4121

Downloaded from cancerres.aacrjournals.org on July 14, 2011 Copyright © 1994 American Association for Cancer Research

schedule

(7).

5CHEDULE DEPENDENCY OF ORAL JM216

ACKNOWLEDGMENTS

10. Delaflor-Weiss, E., Uziely, B., and Muggia, F. M. Protacted drug infusions in cancer treatment: an appraisal of 5-fluorouradil, doxorubicin and platinums. Ann. OncoL, 4: 723—733,1993. 11. Gandara, D. R., Crowley, J., Livingstone, R. B., Perez, E. A., Taylor, C. W., Weiss,

Thanks are due to the Royal Marsden Hospital Hematology for processing

the blood counts.

G., Neefe, J. R, Hutchins,L F., Roach,R. W., Grunberg,S. M., Braun,T. J., Natale, R. B., and Balcerzak, S. P. Evaluation of cisplatin intensity in metastatic non-small cell lung cancer: a phase III study of the Southwest oncology group. J. Clin. Oncol.,

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11: 873—878,1993. 12. Blumenreich, M. S., Woodcock, T. M., Jones, M., Richman, S. P., Gentile, P. S.,

ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug.

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2. Harrap, K. R., Murrer, B. A., Giandomenico, C., Morgan, S. E., Kelland, L R., Jones, M., Goddard,P. M., and Schurig, J. Ammine/amineplatinum(lV)platinumdicar boxylates: a novel class of complexes which circumvent intrinsic cisplatin resistance.

In: S. B. Howell(ed.),PlatinumandOtherMetalCoordination CompoundsinCancer Chemotherapy, pp. 391—399.New York: Plenum Publishing Corp., 1991. 3. McKeage, M. J., Morgan, S. E., Boxall, F. E., Murrer, B. A., Hard, G. C., and Harrap,

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13. Kovach, J. S., Moertel, C. G., Schutt, A. J., Reitemeier, R. G., and Hahn, R. G. Phase

II study of cis-diamminedicMoroplafinum (NSC-119875) in advancedcarcinomaof

the largebowel.CancerChemother.Rep.,57: 357—359, 1973. 14. Krakoff, I. H. Nephrotoxicity of cis-dichlorodiammineplatinum(ll).

15. Higby, D. J., Wallace, H. J., and Holland, J. F. cis-diamminedichloroplatinum (NSC-119875): a phase I study. Cancer Chemother. Rep., 57: 459—463, 1973.

16. Harrap,K. R., Jones, M., Siracky,J., Pollard,L A.. and Kelland,K. R. The establishment, characterization and calibration of human ovarian carcinoma xc nografts for the evaluation ofnovelplatinum anticancer drugs. Ann. Oncol., 1: 65—76, 1990. 17. Goddard, P. M., Valenti, M. R., and Harrap, K. R. The role of murine tumour models

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